Phenotypes associated with the disease mitochondrial DNA depletion syndrome 6 (hepatocerebral type) (OMIM:256810):
- Encephalopathy (HP:0001298): Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state. Evidence: PCS. Frequency: 3/17. (PMID:23714749)
- Nephrocalcinosis (HP:0000121): Nephrocalcinosis is the deposition of calcium salts in renal parenchyma. Evidence: PCS. Frequency: 1/4. (PMID:27536553)
- Peripheral axonal neuropathy (HP:0003477): An abnormality characterized by disruption of the normal functioning of peripheral axons. Evidence: PCS. Frequency: 4/4. (PMID:24190800;PMID:22508010;PMID:34979697;PMID:22964873)
- Hearing impairment (HP:0000365): A decreased magnitude of the sensory perception of sound. Evidence: PCS. Frequency: 1/1. (PMID:22964873)
- Painless fractures due to injury (HP:0002661): An increased tendency to fractures following trauma, with fractures occurring without pain. Evidence: IEA. (OMIM:256810)
- Dystonia (HP:0001332): An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk. Evidence: PCS. Frequency: 11/13. (PMID:18695062;OMIM:256810)
- Mitochondrial depletion (HP:0030059): An abnormal reduction in mitochondrial DNA content of cells. Evidence: PCS. Frequency: 7/7. (PMID:20074988)
- Short stature (HP:0004322): A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms). Evidence: IEA. (OMIM:256810)
- Hypertyrosinemia (HP:0003231): An increased concentration of tyrosine in the blood. Evidence: PCS. Frequency: 4/4. (PMID:18695062;PMID:31664948;PMID:22824774)
- Gait imbalance (HP:0002141). Evidence: PCS. Frequency: 1/1. (PMID:26437932)
- Gastroesophageal reflux (HP:0002020): A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter. Evidence: PCS. Frequency: 3/7. (PMID:20074988)
- Infantile onset (HP:0003593): Onset of signs or symptoms of disease between 28 days to one year of life. Evidence: PCS. Frequency: 34/48. (PMID:18695062;PMID:33486010;PMID:23829229;PMID:29318572;PMID:20074988;PMID:28209105;PMID:27536553;PMID:16909392;PMID:25129007;PMID:23714749;PMID:18329934;PMID:24894789)
- Fasciculations (HP:0002380): Fasciculations are observed as small, local, involuntary muscle contractions (twitching) visible under the skin. Fasciculations result from increased irritability of an axon (which in turn is often a manifestation of disease of a motor neuron). This leads to sporadic discharges of all the muscle fibers controlled by the axon in isolation from other motor units. Evidence: PCS. Frequency: 2/3. (PMID:23829229;PMID:22824774)
- Generalized hypotonia (HP:0001290): Generalized muscular hypotonia (abnormally low muscle tone). Evidence: PCS. Frequency: 1/1. (PMID:18329934)
- Hypoalbuminemia (HP:0003073): The concentration of albumin in the blood circulation is below the lower limit of normal. Evidence: PCS. Frequency: 3/4. (PMID:29318572;PMID:28209105;PMID:22824774;PMID:28673863)
- Osteomyelitis leading to amputation due to slow healing fractures (HP:0005010). Evidence: TAS. (OMIM:256810)
- Impaired executive functioning (HP:0033051): A disturbance of executive functioning, which is broadly defined as the set of abilities that allow for the planning, executing, monitoring, and self-correcting of goal-directed behavior while inhibiting task-irrelevant behavior. At least some degree of executive skill is needed to complete most cognitive tasks, and deficits in executive abilities are central to many clinical conditions, including fronto-temporal dementia. Evidence: PCS. Frequency: 1/3. (PMID:24190800;PMID:26437932;PMID:28673863)
- Nystagmus (HP:0000639): Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms. Evidence: PCS. Frequency: 12/14. (PMID:18695062;PMID:23829229;OMIM:256810)
- Distal sensory impairment (HP:0002936): An abnormal reduction in sensation in the distal portions of the extremities. Evidence: PCS. Frequency: 3/6. (PMID:16909392)
- Diffuse leukoencephalopathy (HP:0006994). Evidence: PCS. Frequency: 2/6. (PMID:16909392)
- Increased susceptibility to fractures (HP:0002659): An abnormally increased tendency to fractures of bones caused by an abnormal reduction in bone strength that is generally associated with an increased risk of fracture. Evidence: TAS. (OMIM:256810)
- Muscle weakness (HP:0001324): Reduced strength of muscles. Evidence: PCS. Frequency: 5/9. (PMID:23829229;PMID:20074988;PMID:31664948)
- Proximal tubulopathy (HP:0000114): Dysfunction of the proximal tubule, which is the portion of the duct system of the nephron of the kidney which leads from Bowman's capsule to the loop of Henle. Evidence: PCS. Frequency: 3/7. (PMID:20074988)
- Constipation (HP:0002019): Infrequent or difficult evacuation of feces. Evidence: PCS. Frequency: 1/1. (PMID:22964873)
- Ophthalmoparesis (HP:0000597): Ophthalmoplegia is a paralysis or weakness of one or more of the muscles that control eye movement. Evidence: PCS. Frequency: 1/2. (PMID:26437932;PMID:22964873)
- Neonatal onset (HP:0003623): Onset of signs or symptoms of disease within the first 28 days of life. Evidence: PCS. Frequency: 8/17. (PMID:18695062;PMID:23829229;PMID:20074988;PMID:31664948;PMID:22824774)
- Incoordination (HP:0002311): A deficit in coordination of muscle movements. Coordination is defined as the orchestrated movement of multiple body parts as required to accomplish intended actions, like walking. Evidence: PCS. Frequency: 1/1. (PMID:28673863)
- Recurrent corneal erosions (HP:0000495): The presence of recurrent corneal epithelial erosions. Although most corneal epithelial defects heal quickly, some may show recurrent ulcerations. Evidence: PCS. (PMID:16909392)
- Elevated circulating aspartate aminotransferase concentration (HP:0031956): The concentration of aspartate aminotransferase (AST) in the blood circulation is above the upper limit of normal. Evidence: PCS. Frequency: 21/24. (PMID:23829229;PMID:27536553;PMID:28209105;PMID:22824774;PMID:26437932;PMID:24894789;PMID:34035203;PMID:18695062;PMID:29318572;PMID:31664948;PMID:16909392;PMID:34979697;PMID:18329934)
- Microcephaly (HP:0000252): Head circumference below 2 standard deviations below the mean for age and gender. Evidence: PCS. Frequency: 4/26. (PMID:18695062;PMID:20074988;PMID:23714749;PMID:24894789)
- Impaired distal proprioception (HP:0006858): A loss or impairment of the sensation of the relative position of parts of the body and joint position occurring at distal joints. Evidence: PCS. Frequency: 6/6. (PMID:24190800;PMID:22508010;PMID:34979697;PMID:28673863;PMID:26437932)
- Decreased activity of mitochondrial complex III (HP:0011924): A reduction in the activity of the mitochondrial respiratory chain complex III, which is part of the electron transport chain in mitochondria. Evidence: PCS. Frequency: 1/1. (PMID:16909392)
- Poor suck (HP:0002033): An inadequate sucking reflex, resulting in the difficult of newborns to be breast-fed. Evidence: PCS. Frequency: 2/2. (PMID:31664948)
- Increased circulating lactate concentration (HP:0002151): Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35). Evidence: PCS. Frequency: 29/40. (PMID:18695062;PMID:29318572;PMID:20074988;PMID:27536553;PMID:22824774;PMID:25129007;PMID:26437932;PMID:34979697;PMID:23714749;PMID:28673863;PMID:22964873;PMID:24894789)
- Decreased activity of mitochondrial complex I (HP:0011923): A reduction in the activity of the mitochondrial respiratory chain complex I, which is part of the electron transport chain in mitochondria. Evidence: PCS. Frequency: 5/8. (PMID:16909392;PMID:23714749)
- Claw toe deformity (HP:0034397): Claw toes are characterized by hyperextension at the metatarsal-phalangeal joints and flexion of the interphalangeal joints. Evidence: PCS. Frequency: 1/1. (PMID:22508010)
- Depletion of mitochondrial DNA in liver (HP:0006581): An abnormal reduction in the number of mitochondria in hepatocytes. Evidence: PCS. Frequency: 15/15. (PMID:18695062;PMID:20074988;PMID:22824774;PMID:16909392;PMID:23714749)
- Reye syndrome-like episodes (HP:0006582): Repeated occurrences of acute noninflammatory encephalopathy and fatty degenerative liver failure. Evidence: IEA. (OMIM:256810)
- Autosomal recessive inheritance (HP:0000007): A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele). Evidence: PCS. (PMID:16582910)
- Pancreatitis (HP:0001733): The presence of inflammation in the pancreas. Evidence: PCS. Frequency: 2/7. (PMID:20074988)
- Weak cry (HP:0001612). Evidence: PCS. Frequency: 1/1. (PMID:31664948)
- Hepatic steatosis (HP:0001397): Steatosis is a term used to denote lipid accumulation within hepatocytes. Evidence: PCS. Frequency: 16/23. (PMID:18695062;PMID:27536553;PMID:22508010;PMID:16909392;PMID:23714749;PMID:25129007)
- Cholestasis (HP:0001396): Impairment of bile flow due to obstruction in bile ducts. Evidence: PCS. Frequency: 13/13. (PMID:18695062;PMID:33486010;PMID:23829229;PMID:20074988;PMID:27536553;PMID:16909392;PMID:23714749)
- Congenital onset (HP:0003577): A phenotypic abnormality that is present at birth. Evidence: PCS. Frequency: 6/17. (PMID:23714749)
- Hepatic failure (HP:0001399). Evidence: PCS. Frequency: 34/44. (PMID:18695062;PMID:23829229;PMID:20074988;PMID:31664948;PMID:27536553;PMID:16909392;PMID:22824774;PMID:23714749;PMID:34979697;PMID:25129007)
- Polyneuropathy (HP:0001271): A generalized disorder of peripheral nerves. Evidence: PCS. Frequency: 3/3. (PMID:33486010;PMID:23829229;PMID:18329934)
- Cirrhosis (HP:0001394): A chronic disorder of the liver in which liver tissue becomes scarred and is partially replaced by regenerative nodules and fibrotic tissue resulting in loss of liver function. Evidence: PCS. Frequency: 11/32. (PMID:33486010;PMID:20074988;PMID:24190800;PMID:31664948;PMID:28209105;PMID:22508010;PMID:16909392;PMID:23714749;PMID:18329934)
- Hepatomegaly (HP:0002240): Abnormally increased size of the liver. Evidence: PCS. Frequency: 24/35. (PMID:33486010;PMID:23829229;PMID:20074988;PMID:24190800;PMID:27536553;PMID:22508010;PMID:22824774;PMID:26437932;PMID:24894789;PMID:34035203;PMID:18695062;PMID:29318572;PMID:16909392;PMID:28673863;PMID:34979697;PMID:25129007)
- Pigmentary retinopathy (HP:0000580): An abnormality of the retina characterized by pigment deposition. It is typically associated with migration and proliferation of macrophages or retinal pigment epithelial cells into the retina; melanin from these cells causes the pigmentary changes. Pigmentary retinopathy is a common final pathway of many retinal conditions and is often associated with visual loss. Evidence: PCS. Frequency: 2/2. (PMID:18329934;PMID:24894789)
- Elevated lactate:pyruvate ratio (HP:0032653): An abnormal increase in the molar ratio of lactate to pyruvate in the blood circulation. Evidence: PCS. Frequency: 5/6. (PMID:27536553;PMID:34979697;PMID:34035203)
- Motor delay (HP:0001270): A type of Developmental delay characterized by a delay in acquiring motor skills. Evidence: PCS. Frequency: 4/8. (PMID:16909392;PMID:26437932)
- Increased serum bile acid concentration (HP:0012202): An increase in the concentration of bile acid in the blood. Evidence: PCS. Frequency: 2/2. (PMID:18695062;PMID:23829229)
- Muscle flaccidity (HP:0010547): A type of paralysis in which a muscle becomes soft and yields to passive stretching, which results from loss of all or practically all peripheral motor nerves that innervated the muscle. Muscle tone is reduced and the affected muscles undergo extreme atrophy within months of the loss of innervation. Evidence: PCS. Frequency: 1/1. (PMID:28673863)
- Elevated circulating alanine aminotransferase concentration (HP:0031964): An abnormally high concentration in the circulation of alanine aminotransferase (ALT). Evidence: PCS. Frequency: 21/24. (PMID:23829229;PMID:27536553;PMID:28209105;PMID:22824774;PMID:26437932;PMID:24894789;PMID:34035203;PMID:18695062;PMID:29318572;PMID:31664948;PMID:16909392;PMID:34979697;PMID:18329934)
- Global proximal tubulopathy (HP:0012573): A type of proximal renal tubulopathy characterized by resorption defects leading to glycosuria, aminoaciduria, tubular proteinuria, renal hypophosphatemia, and urate tubular hyporeabsorption with bicarbonate loss and resulting acidosis. Evidence: PCS. Frequency: 1/1. (PMID:18329934)
- Sensorimotor neuropathy (HP:0007141). Evidence: IEA. (OMIM:256810)
- Pain insensitivity (HP:0007021): Inability to perceive painful stimuli. Evidence: TAS. (OMIM:256810)
- Dehydration (HP:0001944). Evidence: PCS. Frequency: 3/3. (PMID:18695062;PMID:23829229;PMID:22824774)
- Dark urine (HP:0040319): An abnormal dark color of the urine. Evidence: PCS. Frequency: 1/2. (PMID:31664948)
- Hypoglycemia (HP:0001943): A decreased concentration of glucose in the blood. Evidence: PCS. Frequency: 25/45. (PMID:18695062;PMID:33486010;PMID:23829229;PMID:29318572;PMID:20074988;PMID:27536553;PMID:28209105;PMID:16909392;PMID:22824774;PMID:26437932;PMID:23714749;PMID:18329934)
- Periventricular leukomalacia (HP:0006970): Periventricular leukomalacia is characterized by diffuse injury of deep cerebral white matter, accompanied in its most severe form by focal necrosis. The neuropathologic hallmarks of PVL are microglial activation and focal and diffuse periventricular depletion of premyelinating oligodendroglia. Evidence: PCS. Frequency: 3/11. (PMID:18695062;PMID:20074988;PMID:18329934)
- Metabolic acidosis (HP:0001942): Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause. Evidence: PCS. Frequency: 5/6. (PMID:16909392)
- Prolonged neonatal jaundice (HP:0006579): Neonatal jaundice refers to a yellowing of the skin and other tissues of a newborn infant as a result of increased concentrations of bilirubin in the blood. Neonatal jaundice affects over half of all newborns to some extent in the first week of life. Prolonged neonatal jaundice is said to be present if the jaundice persists for longer than 14 days in term infants and 21 days in preterm infants. Evidence: PCS. (PMID:16909392)
- Multiple mitochondrial DNA deletions (HP:0003689): The presence of multiple deletions of mitochondrial DNA (mtDNA). Evidence: PCS. Frequency: 2/2. (PMID:22508010;PMID:22964873)
- Myalgia (HP:0003326): Pain in muscle. Evidence: PCS. Frequency: 1/1. (PMID:28673863)
- Diarrhea (HP:0002014): Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day. Evidence: PCS. Frequency: 14/18. (OMIM:256810;PMID:20074988;PMID:24894789)
- Broad-based gait (HP:0002136): An abnormal gait pattern in which persons stand and walk with their feet spaced widely apart. This is often a component of cerebellar ataxia. Evidence: PCS. Frequency: 1/6. (PMID:16909392)
- Dysphagia (HP:0002015): Difficulty in swallowing. Evidence: PCS. Frequency: 0/1. (PMID:28673863)
- Juvenile onset (HP:0003621): Onset of signs or symptoms of disease between the age of 5 and 15 years. Evidence: PCS. Frequency: 5/21. (PMID:22508010;PMID:23714749;PMID:28673863;PMID:26437932)
- Scoliosis (HP:0002650): The presence of an abnormal lateral curvature of the spine. Evidence: PCS. Frequency: 2/2. (PMID:33486010;PMID:26437932)
- Developmental regression (HP:0002376): Loss of developmental skills, as manifested by loss of developmental milestones. Evidence: PCS. Frequency: 1/1. (PMID:18329934)
- Gait disturbance (HP:0001288): The term gait disturbance can refer to any disruption of the ability to walk. Evidence: PCS. Frequency: 1/1. (PMID:26437932)
- Vomiting (HP:0002013): Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions. Evidence: PCS. Frequency: 15/30. (PMID:23829229;OMIM:256810;PMID:23714749;PMID:18329934)
- Respiratory distress (HP:0002098): Respiratory distress is objectively observable as the physical or emotional consequences from the experience of dyspnea. The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea. Evidence: PCS. Frequency: 1/6. (PMID:16909392)
- Impaired vibratory sensation (HP:0002495): A decrease in the ability to perceive vibration. Clinically, this is usually tested with a tuning fork which vibrates at 128 Hz and is applied to bony prominences such as the malleoli at the ankles or the metacarpal-phalangeal joints. There is a slow decay of vibration from the tuning fork. The degree of vibratory sense loss can be crudely estimated by counting the number of seconds that the examiner can perceive the vibration longer than the patient. Evidence: PCS. Frequency: 6/6. (PMID:24190800;PMID:22508010;PMID:28673863;PMID:34979697;PMID:26437932)
- Areflexia (HP:0001284): Absence of neurologic reflexes such as the knee-jerk reaction. Evidence: PCS. Frequency: 8/9. (PMID:22508010;PMID:16909392;PMID:22824774;PMID:26437932;PMID:18329934)
- Increased CSF lactate (HP:0002490): Increased concentration of lactate in the cerebrospinal fluid. Evidence: PCS. Frequency: 1/1. (PMID:23829229)
- Reduced circulating growth hormone concentration (HP:0034323): Concentration of growth hormone in the blood circulation below normal limits. Evidence: PCS. Frequency: 1/17. (PMID:23714749)
- Upper limb asymmetry (HP:0100560): Difference in length or size between the right and left arm. Evidence: PCS. Frequency: 1/1. (PMID:28673863)
- Hypofibrinogenemia (HP:0011900): Decreased concentration of fibrinogen in the blood. Evidence: PCS. Frequency: 1/1. (PMID:28209105)
- Reduced cerebral white matter volume (HP:0034295): An abnormally low volume of the white matter of the brain. Evidence: PCS. Frequency: 1/7. (PMID:20074988)
- Secondary amenorrhea (HP:0000869). Evidence: PCS. Frequency: 1/1. (PMID:24190800)
- Lower limb asymmetry (HP:0100559): A difference in length or diameter between the left and right leg. Evidence: PCS. Frequency: 1/1. (PMID:28673863)
- Ptosis (HP:0000508): The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective). Evidence: PCS. Frequency: 1/1. (PMID:22964873)
- Hyperintensity of cerebral white matter on MRI (HP:0030890): A brighter than expected signal on magnetic resonance imaging emanating from the cerebral white matter. Evidence: PCS. Frequency: 5/7. (PMID:18695062;PMID:24190800;PMID:31664948;PMID:22508010;PMID:22824774;PMID:28673863;PMID:34035203)
- Peripheral neuropathy (HP:0009830): Peripheral neuropathy is a general term for any disorder of the peripheral nervous system. The main clinical features used to classify peripheral neuropathy are distribution, type (mainly demyelinating versus mainly axonal), duration, and course. Evidence: PCS. Frequency: 8/29. (PMID:20074988;PMID:16909392;PMID:23714749)
- Decreased activity of mitochondrial complex IV (HP:0008347): A reduction in the activity of the mitochondrial respiratory chain complex IV, which is part of the electron transport chain in mitochondria. Evidence: PCS. Frequency: 6/8. (PMID:16909392;PMID:23714749)
- Increased CSF protein concentration (HP:0002922): Increased concentration of protein in the cerebrospinal fluid. Evidence: PCS. Frequency: 1/1. (PMID:22508010)
- Positive Romberg sign (HP:0002403): The patient stands with the feet placed together and balance and is asked to close his or her eyes. A loss of balance upon eye closure is a positive Romberg sign and is interpreted as indicating a deficit in proprioception. Evidence: PCS. Frequency: 2/2. (PMID:28673863;PMID:34979697)
- EMG: myopathic abnormalities (HP:0003458): The presence of abnormal electromyographic patterns indicative of myopathy, such as small-short polyphasic motor unit potentials. Evidence: PCS. Frequency: 1/1. (PMID:28673863)
- Progressive (HP:0003676): Applies to a disease manifestation that increases in scope or severity over the course of time, i.e., that worsens with age. Evidence: PCS. (PMID:16909392)
- Delayed CNS myelination (HP:0002188): Delayed myelination in the central nervous system. Evidence: PCS. Frequency: 1/4. (PMID:18695062;PMID:27536553)
- Mild intellectual disability (HP:0001256): Mild intellectual disability (ID) is defined as a type of ID characterized by mildly sub-average adaptive functioning and intellectual functioning, with an intelligence quotient (IQ) the range of 50-69. Evidence: PCS. Frequency: 1/4. (PMID:34023347;PMID:24190800;PMID:22508010;PMID:26437932)
- Moderate intellectual disability (HP:0002342): Moderate intellectual disability (ID) is defined as a type of ID characterized by moderately sub-average adaptive functioning and intellectual functioning, with an intelligence quotient (IQ) the range of 35-49. Evidence: PCS. Frequency: 0/4. (PMID:34023347;PMID:24190800;PMID:22508010;PMID:26437932)
- Seizure (HP:0001250): A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Evidence: PCS. Frequency: 4/12. (PMID:18695062;PMID:31664948;PMID:16909392;PMID:34035203;PMID:18329934)
- Elevated circulating alkaline phosphatase concentration (HP:0003155): Abnormally increased serum levels of alkaline phosphatase activity. Evidence: PCS. Frequency: 4/4. (PMID:31664948;PMID:28209105;PMID:22824774;PMID:24894789)
- Elevated brain lactate level by MRS (HP:0012707): An increase in the level of lactate in the brain identified by magnetic resonance spectroscopy (MRS). Evidence: PCS. Frequency: 1/1. (PMID:18695062)
- Hypotonia (HP:0001252): Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist. Evidence: PCS. Frequency: 21/33. (PMID:18695062;PMID:23829229;PMID:27536553;PMID:22508010;PMID:16909392;PMID:22824774;PMID:23714749;PMID:24894789;PMID:34035203)
- Ataxia (HP:0001251): Ataxia refers to impaired coordination of voluntary muscle movement. Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly). Evidence: TAS. (OMIM:256810)
- Distal muscle weakness (HP:0002460): Reduced strength of the musculature of the distal extremities. Evidence: PCS. Frequency: 5/7. (PMID:22508010;PMID:16909392)
- Abdominal distention (HP:0003270): Distention of the abdomen. Evidence: PCS. Frequency: 2/7. (PMID:16909392;PMID:25129007)
- Appendicular hypotonia (HP:0012389): Muscular hypotonia of one or more limbs. Evidence: PCS. Frequency: 1/1. (PMID:34979697)
- Depletion of mitochondrial DNA in muscle tissue (HP:0009141). Evidence: PCS. Frequency: 9/12. (PMID:20074988;PMID:22824774;PMID:23714749;PMID:18329934)
- Depression (HP:0000716): Frequently experiencing feelings of being down, miserable, and/or hopeless; struggling to recover from these moods; having a pessimistic outlook on the future; feeling a pervasive sense of shame; having a low self-worth; experiencing thoughts of suicide and engaging in suicidal behavior. Evidence: PCS. Frequency: 1/1. (PMID:22964873)
- Childhood onset (HP:0011463): Onset of disease at the age of between 1 and 5 years. Evidence: PCS. Frequency: 4/23. (PMID:34023347;PMID:27536553;PMID:23714749;PMID:34035203)
- Young adult onset (HP:0011462): Onset of disease at the age of between 16 and 40 years. Evidence: PCS. Frequency: 3/3. (PMID:24190800;PMID:34979697;PMID:22964873)
- Foot dorsiflexor weakness (HP:0009027): Weakness of the muscles responsible for dorsiflexion of the foot, that is, of the movement of the toes towards the shin. The foot dorsiflexors include the tibialis anterior, the extensor hallucis longus, the extensor digitorum longus, and the peroneus tertius muscles. Evidence: PCS. Frequency: 2/2. (PMID:22508010;PMID:34979697)
- Periportal fibrosis (HP:0001405): The presence of fibrosis affecting the interlobular stroma of liver. Evidence: PCS. Frequency: 2/2. (PMID:18695062)
- Hepatocellular necrosis (HP:0001404). Evidence: PCS. Frequency: 1/6. (PMID:16909392)
- Acute hepatic failure (HP:0006554): Hepatic failure refers to the inability of the liver to perform its normal synthetic and metabolic functions, which can result in coagulopathy and alteration in the mental status of a previously healthy individual. Hepatic failure is defined as acute if there is onset of encephalopathy within 8 weeks of the onset of symptoms in a patient with a previously healthy liver. Evidence: PCS. Frequency: 11/11. (OMIM:256810;PMID:34023347)
- Corneal scarring (HP:0000559). Evidence: PCS. Frequency: 2/3. (PMID:16909392)
- Intrahepatic cholestasis (HP:0001406): Impairment of bile flow due to obstruction in the small bile ducts within the liver. Evidence: PCS. Frequency: 3/3. (PMID:29318572;PMID:28209105;PMID:25129007)
- Gastrointestinal dysmotility (HP:0002579): Abnormal intestinal contractions, such as spasms and intestinal paralysis, related to the loss of the ability of the gut to coordinate muscular activity because of endogenous or exogenous causes. Evidence: PCS. Frequency: 1/1. (PMID:22964873)
- Pes planus (HP:0001763): A foot where the longitudinal arch of the foot is in contact with the ground or floor when the individual is standing; or, in a patient lying supine, a foot where the arch is in contact with the surface of a flat board pressed against the sole of the foot by the examiner with a pressure similar to that expected from weight bearing; or, the height of the arch is reduced. Evidence: PCS. Frequency: 1/1. (PMID:34979697)
- Intellectual disability (HP:0001249): The term intellectual disability or intellectual developmental disorder is used to describe significantly sub-average intellectual and adaptive functioning based on clinical assessment and as measured by individually administered, appropriately normed, standardized and validated tests of intellectual functioning and adaptive behavior, with onset during the developmental period from infancy through adolescence. Evidence: PCS. Frequency: 0/1. (PMID:34979697)
- Jaundice (HP:0000952): Yellow pigmentation of the skin due to bilirubin, which in turn is the result of increased bilirubin concentration in the bloodstream. Evidence: PCS. Frequency: 23/35. (PMID:18695062;PMID:29318572;PMID:31664948;PMID:16909392;PMID:25129007;PMID:23714749;PMID:24894789;PMID:18329934)
- Macrovesicular hepatic steatosis (HP:0001403): A form of hepatic steatosis characterized by the presence of large, lipid-laden vesicles in the affected hepatocytes. Evidence: PCS. Frequency: 3/8. (PMID:28209105;PMID:16909392;PMID:24894789)
- Retinal dystrophy (HP:0000556): Retinal dystrophy is an abnormality of the retina associated with a hereditary process. Retinal dystrophies are defined by their predominantly monogenic inheritance and they are frequently associated with loss or dysfunction of photoreceptor cells as a primary or secondary event. Evidence: PCS. Frequency: 1/1. (PMID:18329934)
- Exercise intolerance (HP:0003546): A functional motor deficit where individuals whose responses to the challenges of exercise fail to achieve levels considered normal for their age and gender. Evidence: PCS. Frequency: 1/1. (PMID:22964873)
- Generalized amyotrophy (HP:0003700): Generalized (diffuse, unlocalized) amyotrophy (muscle atrophy) affecting multiple muscles. Evidence: PCS. Frequency: 1/1. (PMID:22824774)
- Hammertoe (HP:0001765): Hyperextension of the metatarsal-phalangeal joint with hyperflexion of the proximal interphalangeal (PIP) joint. Evidence: PCS. Frequency: 1/1. (PMID:34979697)
- Hepatocellular carcinoma (HP:0001402): A kind of neoplasm of the liver that originates in hepatocytes and presents macroscopically as a soft and hemorrhagic tan mass in the liver. Evidence: PCS. Frequency: 1/6. (PMID:16909392)
- Hyporeflexia (HP:0001265): Reduction of neurologic reflexes such as the knee-jerk reaction. Evidence: PCS. Frequency: 4/9. (PMID:29318572;PMID:23829229;PMID:16909392;PMID:28673863)
- Progressive muscle weakness (HP:0003323). Evidence: PCS. Frequency: 1/6. (PMID:16909392)
- Skeletal muscle atrophy (HP:0003202): The presence of skeletal muscular atrophy (which is also known as amyotrophy). Evidence: PCS. Frequency: 1/6. (PMID:16909392)
- Parkinsonism (HP:0001300): Characteristic neurologic anomaly resulting from degeneration of dopamine-generating cells in the substantia nigra, a region of the midbrain, characterized clinically by shaking, rigidity, slowness of movement and difficulty with walking and gait. Evidence: PCS. Frequency: 1/1. (PMID:22964873)
- Ragged-red muscle fibers (HP:0003200): An abnormal appearance of muscle fibers observed on muscle biopsy. Ragged red fibers can be visualized with Gomori trichrome staining as irregular and intensely red subsarcolemmal zones, whereas the normal myofibrils are green. The margins of affect fibers appear red and ragged. The ragged-red is due to the accumulation of abnormal mitochondria below the plasma membrane of the muscle fiber, leading to the appearance of a red rim and speckled sarcoplasm. Evidence: PCS. Frequency: 0/4. (PMID:18695062;PMID:22508010;PMID:28673863;PMID:34979697)
- Ascites (HP:0001541): Accumulation of fluid in the peritoneal cavity (between the layers of the peritoneum that lines the abdomen). Evidence: PCS. Frequency: 4/12. (PMID:23829229;PMID:16909392;PMID:25129007;PMID:24894789)
- Bradycardia (HP:0001662): A slower than normal heart rate (in adults, slower than 60 beats per minute). Evidence: PCS. Frequency: 1/1. (PMID:22964873)
- Memory impairment (HP:0002354): An impairment of memory as manifested by a reduced ability to remember things such as dates and names, and increased forgetfulness. Evidence: PCS. Frequency: 1/1. (PMID:24190800)
- Feeding difficulties (HP:0011968): Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it. Evidence: PCS. Frequency: 7/19. (PMID:23829229;PMID:22824774;PMID:23714749)
- Impaired distal tactile sensation (HP:0006937): A reduced sense of touch (tactile sensation) on the skin of the distal limbs. This is usually tested with a wisp of cotton or a fine camel's hair brush, by asking patients to say 'now' each time they feel the stimulus. Evidence: PCS. Frequency: 10/12. (PMID:24190800;PMID:22508010;PMID:16909392;PMID:28673863;PMID:26437932;PMID:34979697)
- Dysarthria (HP:0001260): Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed. Evidence: PCS. Frequency: 0/1. (PMID:28673863)
- Global developmental delay (HP:0001263): A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age. Evidence: PCS. Frequency: 19/44. (PMID:33486010;PMID:20074988;PMID:24190800;PMID:27536553;PMID:22508010;PMID:26437932;PMID:34035203;PMID:31664948;PMID:16909392;PMID:34979697;PMID:28673863;PMID:23714749;PMID:18329934)
- Delayed gross motor development (HP:0002194): A type of motor delay characterized by a delay in acquiring the ability to control the large muscles of the body for walking, running, sitting, and crawling. Evidence: PCS. Frequency: 1/3. (PMID:24190800;PMID:34979697;PMID:34035203)
- Elevated gamma-glutamyltransferase level (HP:0030948): Increased level of the enzyme gamma-glutamyltransferase (GGT). GGT is mainly present in kidney, liver, and pancreatic cells, but small amounts are present in other tissues. Evidence: PCS. Frequency: 7/12. (PMID:18695062;PMID:23829229;PMID:28209105;PMID:16909392;PMID:26437932;PMID:24894789)
- Increased circulating ferritin concentration (HP:0003281): Increased concentration of ferritin in the blood circulation. Evidence: PCS. Frequency: 2/2. (PMID:23829229;PMID:24894789)
- Conjugated hyperbilirubinemia (HP:0002908). Evidence: PCS. Frequency: 9/12. (PMID:18695062;PMID:29318572;PMID:28209105;PMID:22824774;PMID:16909392;PMID:28673863;PMID:34979697;PMID:34035203)
- Decreased circulating cortisol level (HP:0008163): Abnormally reduced concentration of cortisol in the blood. Evidence: PCS. Frequency: 1/17. (PMID:23714749)
- Hyperbilirubinemia (HP:0002904): An increased amount of bilirubin in the blood. Evidence: PCS. Frequency: 1/1. (PMID:31664948)
- Scaling skin (HP:0040189): Refers to the loss of the outer layer of the epidermis in large, scale-like flakes. Evidence: PCS. Frequency: 1/1. (PMID:22824774)
- Loss of ambulation (HP:0002505): Inability to walk in a person who previous had the ability to walk. Evidence: PCS. Frequency: 2/6. (PMID:16909392)
- Respiratory insufficiency due to muscle weakness (HP:0002747). Evidence: PCS. Frequency: 1/1. (PMID:28209105)
- Absent Achilles reflex (HP:0003438): Absence of the Achilles reflex (also known as the ankle jerk reflex), which can normally be elicited by tapping the tendon is tapped while the foot is dorsiflexed. Evidence: PCS. Frequency: 3/3. (PMID:24190800;PMID:28673863;PMID:26437932)
- Type II diabetes mellitus (HP:0005978): A type of diabetes mellitus initially characterized by insulin resistance and hyperinsulinemia and subsequently by glucose interolerance and hyperglycemia. Evidence: PCS. Frequency: 1/1. (PMID:22964873)
- Microvesicular hepatic steatosis (HP:0001414): A form of hepatic steatosis characterized by the presence of small, lipid-laden vesicles in the affected hepatocytes. Evidence: PCS. Frequency: 14/14. (PMID:18695062;PMID:29318572;OMIM:256810;PMID:28209105;PMID:24894789)
- Micronodular cirrhosis (HP:0001413): A type of cirrhosis characterized by the presence of small regenerative nodules. Evidence: PCS. Frequency: 1/6. (PMID:16909392)
- Steppage gait (HP:0003376): An abnormal gait pattern that arises from weakness of the pretibial and peroneal muscles due to a lower motor neuron lesion. Affected patients have footdrop and are unable to dorsiflex and evert the foot. The leg is lifted high on walking so that the toes clear the ground, and there may be a slapping noise when the foot strikes the ground again. Evidence: PCS. Frequency: 1/1. (PMID:24190800)
- Abnormality of the coagulation cascade (HP:0003256): An abnormality of the coagulation cascade, which is comprised of the contact activation pathway (also known as the intrinsic pathway) and the tissue factor pathway (also known as the extrinsic pathway) as well as cofactors and regulators. Evidence: PCS. Frequency: 4/19. (PMID:23829229;PMID:25129007;PMID:23714749)
- Corneal ulceration (HP:0012804): Disruption of the epithelial layer of the cornea with involvement of the underlying stroma. Evidence: PCS. Frequency: 2/6. (PMID:16909392)
- Antinuclear antibody positivity (HP:0003493): The presence of autoantibodies in the serum that react against nuclei or nuclear components. Evidence: PCS. Frequency: 0/1. (PMID:34979697)
- Severe intellectual disability (HP:0010864): Severe intellectual disability (ID) is defined as a type of ID characterized by severely sub-average adaptive functioning and intellectual functioning, with an intelligence quotient (IQ) the range of 20-34. Evidence: PCS. Frequency: 0/4. (PMID:34023347;PMID:24190800;PMID:22508010;PMID:26437932)
- Prolonged prothrombin time (HP:0008151): Increased time to coagulation in the prothrombin time test, which is a measure of the extrinsic pathway of coagulation. The results of the prothrombin time test are often expressed in terms of the International normalized ratio (INR), which is calculated as a ratio of the patient's prothrombin time (PT) to a control PT standardized for the potency of the thromboplastin reagent developed by the World Health Organization (WHO) using the formula: INR is equal to Patient PT divided by Control PT. Evidence: PCS. Frequency: 13/15. (PMID:18695062;PMID:29318572;PMID:24190800;PMID:31664948;PMID:28209105;PMID:16909392;PMID:22824774;PMID:34979697;PMID:28673863;PMID:24894789;PMID:34035203)
- Autoamputation of digits (HP:0007460): The spontaneous detachment of a digit (finger or toe) from the body due to long standing pathology. Evidence: TAS. (OMIM:256810)
- Failure to thrive (HP:0001508): Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm. Evidence: PCS. Frequency: 25/46. (PMID:23829229;PMID:20074988;PMID:28209105;PMID:22824774;PMID:34035203;PMID:24894789;PMID:18695062;PMID:29318572;PMID:31664948;PMID:16909392;PMID:34979697;PMID:23714749;PMID:18329934)
- Lower limb muscle weakness (HP:0007340): Weakness of the muscles of the legs. Evidence: PCS. Frequency: 8/10. (PMID:16909392;PMID:34979697;PMID:26437932;PMID:22964873)
- Ankle weakness (HP:0031374): Reduced strength of the muscles that lift or otherwise move the foot at the ankle. Evidence: PCS. Frequency: 2/2. (PMID:24190800;PMID:34979697)
- Elevated circulating alpha-fetoprotein concentration (HP:0006254): The concentration of alpha-fetoprotein in the blood circulation is above the upper limit of normal. Evidence: PCS. Frequency: 4/6. (PMID:18695062;PMID:31664948;PMID:28209105;PMID:26437932)
- Recurrent hypoglycemia (HP:0001988): Recurrent episodes of decreased concentration of glucose in the blood. Evidence: PCS. Frequency: 2/6. (PMID:16909392)
- Weakness of the intrinsic hand muscles (HP:0009005). Evidence: PCS. Frequency: 1/1. (PMID:34979697)
- Hyperammonemia (HP:0001987): An increased concentration of ammonia in the blood. Evidence: PCS. Frequency: 4/5. (PMID:18695062;PMID:24190800;PMID:22824774;PMID:25129007;PMID:34979697)
- Lacticaciduria (HP:0003648): An increased concentration of lactic acid in the urine. Evidence: PCS. Frequency: 1/1. (PMID:23829229)
- Unsteady gait (HP:0002317). Evidence: PCS. Frequency: 1/1. (PMID:26437932)
- Reticular hyperpigmentation (HP:0007588): Increased pigmentation of the skin with a netlike (reticular) pattern. Evidence: PCS. Frequency: 1/1. (PMID:22824774)
- Intrinsic hand muscle atrophy (HP:0008954): Atrophy of the intrinsic muscle groups of the hand, comprising the thenar and hypothenar muscles; the interossei muscles; and the lumbrical muscles. Evidence: PCS. Frequency: 3/3. (PMID:24190800;PMID:22508010;PMID:26437932)
- Splenomegaly (HP:0001744): Abnormal increased size of the spleen. Evidence: PCS. Frequency: 3/7. (PMID:29318572;PMID:24190800;PMID:25129007;PMID:34979697;PMID:28673863;PMID:24894789)
- Lactic acidosis (HP:0003128): An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids. Evidence: PCS. Frequency: 21/23. (PMID:18695062;PMID:23829229;PMID:20074988;PMID:24190800;PMID:16909392;PMID:18329934;PMID:34035203)
- Prolonged partial thromboplastin time (HP:0003645): Increased time to coagulation in the partial thromboplastin time (PTT) test, a measure of the intrinsic and common coagulation pathways. Phospholipid, and activator, and calcium are mixed into an anticoagulated plasma sample, and the time is measured until a thrombus forms. Evidence: PCS. Frequency: 7/7. (PMID:29318572;PMID:31664948;PMID:28209105;PMID:22824774;PMID:24894789)
- Axial hypotonia (HP:0008936): Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk. Evidence: PCS. Frequency: 4/4. (PMID:29318572;PMID:23829229)
- Wide nasal bridge (HP:0000431): Increased breadth of the nasal bridge (and with it, the nasal root). Evidence: PCS. Frequency: 1/4. (PMID:18695062;PMID:22824774)
- Brittle hair (HP:0002299): Fragile, easily breakable hair, i.e., with reduced tensile strength. Evidence: PCS. Frequency: 1/1. (PMID:22824774)
- Increased circulating pyruvate concentration (HP:0003542): The concentration of pyruvate in the blood circulation is above the upper limit of normal. Evidence: PCS. Frequency: 1/3. (PMID:28673863;PMID:26437932)
- Pes cavus (HP:0001761): An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight). Evidence: PCS. Frequency: 0/1. (PMID:22508010)
- Episodic vomiting (HP:0002572): Paroxysmal, recurrent episodes of vomiting. Evidence: PCS. Frequency: 6/12. (PMID:20074988;PMID:27536553;PMID:22824774)
- Cholelithiasis (HP:0001081): Hard, pebble-like deposits that form within the gallbladder. Evidence: PCS. Frequency: 1/1. (PMID:28673863)
- Postural instability (HP:0002172): A tendency to fall or the inability to keep oneself from falling; imbalance. The retropulsion test is widely regarded as the gold standard to evaluate postural instability, Use of the retropulsion test includes a rapid balance perturbation in the backward direction, and the number of balance correcting steps (or total absence thereof) is used to rate the degree of postural instability. Healthy subjects correct such perturbations with either one or two large steps, or without taking any steps, hinging rapidly at the hips while swinging the arms forward as a counterweight. In patients with balance impairment, balance correcting steps are often too small, forcing patients to take more than two steps. Taking three or more steps is generally considered to be abnormal, and taking more than five steps is regarded as being clearly abnormal. Markedly affected patients continue to step backward without ever regaining their balance and must be caught by the examiner (this would be called true retropulsion). Even more severely affected patients fail to correct entirely, and fall backward like a pushed toy soldier, without taking any corrective steps. Evidence: PCS. Frequency: 1/1. (PMID:28673863)
- Decreased number of peripheral myelinated nerve fibers (HP:0003380): A loss of myelinated nerve fibers in the peripheral nervous system (in general, this finding can be observed on nerve biopsy). Evidence: PCS. Frequency: 2/2. (PMID:16909392;PMID:34979697)
- Decreased Achilles reflex (HP:0009072): Decreased intensity of the Achilles reflex (also known as the ankle jerk reflex), which can be elicited by tapping the tendon is tapped while the foot is dorsiflexed. Evidence: PCS. Frequency: 1/1. (PMID:34979697)
- Hypoparathyroidism (HP:0000829): A condition caused by a deficiency of parathyroid hormone characterized by hypocalcemia and hyperphosphatemia. Evidence: PCS. Frequency: 3/24. (PMID:20074988;PMID:23714749)
- Progressive proximal muscle weakness (HP:0009073): Lack of strength of the proximal muscles that becomes progressively more severe. Evidence: PCS. Frequency: 1/1. (PMID:22964873)
- Cytoplasmic antineutrophil antibody positivity (HP:0032230): The presence of autoantibodies in the serum that react against proteins predominantly expressed in cytoplasmic granules of neutrophils. Evidence: PCS. Frequency: 0/1. (PMID:34979697)
- Increased hepatic echogenicity (HP:0031141): Increased echogenicity of liver tissue on sonography, manifested as an increased amount of white on the screen of the sonography device. Evidence: PCS. Frequency: 2/2. (PMID:25129007;PMID:34035203)
- Small for gestational age (HP:0001518): Smaller than normal size according to sex and gestational age related norms, defined as a weight below the 10th percentile for the gestational age. Evidence: PCS. Frequency: 1/10. (PMID:18695062;PMID:23829229;PMID:27536553;PMID:28209105;PMID:22824774)
- Acral ulceration (HP:0006121): A type of digital ulcer that manifests as an open sore on the surface of the skin at the tip of a finger or toe. Evidence: TAS. (OMIM:256810)
- Motor polyneuropathy (HP:0007178). Evidence: PCS. Frequency: 1/4. (PMID:27536553)
- Hypothyroidism (HP:0000821): Deficiency of thyroid hormone. Evidence: PCS. Frequency: 1/17. (PMID:23714749)
- Growth delay (HP:0001510): A deficiency or slowing down of growth pre- and postnatally. Evidence: PCS. Frequency: 3/6. (PMID:16909392)
- Horizontal nystagmus (HP:0000666): Nystagmus consisting of horizontal to-and-fro eye movements. Evidence: PCS. Frequency: 1/4. (PMID:27536553)
- Kidney stone (HP:0000787): Kidney stones (calculi) are mineral concretions in the renal calyces and pelvis that are found free or attached to the renal papillae. Evidence: PCS. Frequency: 1/1. (PMID:22824774)
- Distal lower limb amyotrophy (HP:0008944): Muscular atrophy of distal leg muscles. Evidence: PCS. Frequency: 5/5. (PMID:24190800;PMID:22508010;PMID:16909392;PMID:26437932;PMID:34979697)