Phenotypes associated with the disease mitochondrial DNA depletion syndrome 13 (OMIM:615471):
- 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: 3/3. (PMID:31969900;PMID:32779419)
- Poor head control (HP:0002421): Difficulty to maintain correct position of the head while standing or sitting. Infant head lag is observed when the head seems to flop around or lags posteriorly behind the trunk. Several articles have maintained that head lag should be absent by age 3 to 4 months. Evidence: PCS. Frequency: 4/4. (PMID:27182039;PMID:32559514;PMID:30804983;PMID:32779419)
- Hearing impairment (HP:0000365): A decreased magnitude of the sensory perception of sound. Evidence: PCS. Frequency: 7/52. (PMID:27182039;PMID:28940506;PMID:27743463;PMID:25868664;PMID:23993194;PMID:32779419)
- Strabismus (HP:0000486): A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error. Evidence: PCS. Frequency: 11/52. (PMID:27182039;PMID:28940506;PMID:30804983;PMID:34602956;PMID:25868664;PMID:23993194)
- 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: TAS. Frequency: Occasional (HP:0040283). (OMIM:615471)
- Mitochondrial depletion (HP:0030059): An abnormal reduction in mitochondrial DNA content of cells. Evidence: PCS. Frequency: 18/20. (PMID:27290639;PMID:28940506;PMID:25868664;PMID:23993194)
- 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: PCS. Frequency: 27/53. (PMID:28940506;PMID:27743463;PMID:25868664;PMID:23993194)
- Focal impaired awareness seizure (HP:0002384): Focal impaired awareness seizure (or focal seizure with impaired or lost awareness) is a type of focal-onset seizure characterized by some degree (which may be partial) of impairment of the person's awareness of themselves or their surroundings at any point during the seizure. Evidence: PCS. Frequency: 2/38. (PMID:27182039;PMID:28940506;PMID:27743463;PMID:25868664)
- 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: TAS. (OMIM:615471)
- Infantile onset (HP:0003593): Onset of signs or symptoms of disease between 28 days to one year of life. Evidence: PCS. Frequency: 17/77. (PMID:28940506;PMID:32559514;PMID:30804983;PMID:27743463;PMID:25868664;PMID:23993194)
- Short palpebral fissure (HP:0012745): Distance between the medial and lateral canthi is more than 2 SD below the mean for age (objective); or, apparently reduced length of the palpebral fissures. Evidence: PCS. Frequency: 8/68. (PMID:27290639;PMID:27182039;PMID:28940506;PMID:34602956;PMID:26404457;PMID:27099744;PMID:25868664;PMID:23993194)
- Type 2 muscle fiber predominance (HP:0010602): An abnormal predominance of type II muscle fibers (in general, this feature can only be observed on muscle biopsy). Evidence: PCS. Frequency: 1/1. (PMID:23993193)
- Thin corpus callosum (HP:0033725): An abnormally thin corpus callous, due to atrophy, hypoplasia or agenesis. This term is intended to be used in situations where it is not known if thinning of the corpus callosum (for instance, as visualized by magnetic resonance tomography) is due to abnormal development (e.g. a leukodystrophy) or atrophy following normal development (e.g. neurodegeneration). Evidence: PCS. Frequency: 13/50. (PMID:28940506;PMID:34602956;PMID:27099744;PMID:25868664;PMID:23993194;PMID:32779419)
- Infantile spasms (HP:0012469): Infantile spasms represent a subset of "epileptic spasms". Infantile Spasms are epileptic spasms starting in the first year of life (infancy). Evidence: PCS. Frequency: 1/37. (PMID:28940506;PMID:27743463;PMID:31969900)
- Cataract (HP:0000518): A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule. Evidence: PCS. Frequency: 2/6. (PMID:23993193)
- Nystagmus (HP:0000639): Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms. Evidence: PCS. Frequency: 12/59. (PMID:27182039;PMID:28940506;PMID:30804983;PMID:34602956;PMID:27743463;PMID:25868664;PMID:31969900;PMID:32779419;PMID:23993194)
- Hydrocephalus (HP:0000238): Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation. Evidence: PCS. Frequency: 1/1. (PMID:34602956)
- Leukodystrophy (HP:0002415): Leukodystrophy refers to deterioration of white matter of the brain resulting from degeneration of myelin sheaths in the CNS. Their basic defect is directly related to the synthesis and maintenance of myelin membranes. Symmetric white matter involvement at MRI is a typical finding in patients with leukodystrophies. Evidence: PCS. Frequency: 6/6. (PMID:27743463)
- Hyperalaninemia (HP:0003348): An increased concentration of alanine in the blood. Evidence: PCS. Frequency: 6/6. (PMID:27182039;PMID:34602956;PMID:26404457;PMID:31969900;PMID:32779419)
- Neonatal onset (HP:0003623): Onset of signs or symptoms of disease within the first 28 days of life. Evidence: PCS. Frequency: 57/84. (PMID:27290639;PMID:28940506;PMID:27182039;PMID:27743463;PMID:26404457;PMID:25868664;PMID:27099744;PMID:31969900;PMID:23993194;PMID:32779419)
- Downslanted palpebral fissures (HP:0000494): The palpebral fissure inclination is more than two standard deviations below the mean. Evidence: TAS. (OMIM:615471)
- Microcephaly (HP:0000252): Head circumference below 2 standard deviations below the mean for age and gender. Evidence: PCS. Frequency: 30/63. (PMID:28940506;PMID:23993193;PMID:27743463;PMID:30804983;PMID:31969900;PMID:27099744;PMID:25868664;PMID:23993194)
- Babinski sign (HP:0003487): Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract. Evidence: PCS. Frequency: 1/1. (PMID:27182039)
- 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: 15/36. (PMID:27290639;PMID:28940506;PMID:23993193;PMID:25868664;PMID:23993194)
- Decreased activity of mitochondrial ATP synthase complex (HP:0011925): A reduction in the activity of the mitochondrial proton-transporting ATP synthase complex, which makes ATP via oxidative phosphorylation, and is sometimes described as Complex V of the electron transport chain. Evidence: PCS. Frequency: 8/19. (PMID:27290639;PMID:28940506;PMID:25868664)
- 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: 99/99. (PMID:27290639;PMID:28940506;PMID:27182039;PMID:32559514;PMID:23993193;PMID:32779419;PMID:23993194;PMID:30804983;PMID:30771478;PMID:34602956;PMID:27743463;PMID:31442532;PMID:27099744;PMID:25868664;PMID:31969900)
- 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: 16/36. (PMID:27290639;PMID:28940506;PMID:23993193;PMID:25868664;PMID:23993194)
- 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:23993193)
- Long eyelashes (HP:0000527): Mid upper eyelash length >10 mm or increased length of the eyelashes (subjective). Evidence: PCS. Frequency: 9/66. (PMID:27290639;PMID:28940506;PMID:30804983;PMID:27099744;PMID:25868664;PMID:23993194)
- Optic atrophy (HP:0000648): Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy. Evidence: PCS. Frequency: 8/52. (PMID:28940506;PMID:25868664;PMID:32779419;PMID:23993194)
- Low-set ears (HP:0000369): Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear. Evidence: PCS. Frequency: 15/68. (PMID:27290639;PMID:28940506;PMID:25868664;PMID:31969900;PMID:27099744;PMID:23993194;PMID:32779419)
- Hydronephrosis (HP:0000126): Severe distention of the kidney with dilation of the renal pelvis and calices. Evidence: PCS. Frequency: 1/1. (PMID:31442532)
- Hyperkinetic movements (HP:0002487): Motor hyperactivity with excessive movement of muscles of the body as a whole. Evidence: PCS. Frequency: 1/1. (PMID:27182039)
- Long philtrum (HP:0000343): Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border. Evidence: PCS. Frequency: 12/68. (PMID:27290639;PMID:28940506;PMID:27182039;PMID:30804983;PMID:25868664;PMID:27099744;PMID:23993194;PMID:32779419)
- Cerebellar atrophy (HP:0001272): Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event. Evidence: PCS. Frequency: 9/49. (PMID:28940506;PMID:25868664;PMID:27099744;PMID:32779419;PMID:23993194)
- Hepatomegaly (HP:0002240): Abnormally increased size of the liver. Evidence: PCS. Frequency: 1/2. (PMID:27182039;PMID:32779419)
- Renal tubular acidosis (HP:0001947): Acidosis owing to malfunction of the kidney tubules with accumulation of metabolic acids and hyperchloremia, potentially leading to complications including hypokalemia, hypercalcinuria, nephrolithiasis and nephrocalcinosis. Evidence: TAS. Frequency: Occasional (HP:0040283). (OMIM:615471)
- Concave nasal ridge (HP:0011120): Nasal ridge curving posteriorly to an imaginary line that connects the nasal root and tip. Evidence: TAS. (OMIM:615471)
- Elevated urinary 3-hydroxybutyric acid (HP:0040155): An increased amount of 3-hydroxybutyric acid in the urine. Evidence: PCS. Frequency: 1/1. (PMID:32559514)
- Reduced visual acuity (HP:0007663). Evidence: PCS. Frequency: 7/51. (PMID:28940506;PMID:25868664;PMID:23993194)
- Ventriculomegaly (HP:0002119): An increase in size of the ventricular system of the brain. Evidence: PCS. Frequency: 18/59. (PMID:27182039;PMID:28940506;PMID:23993193;PMID:34602956;PMID:30804983;PMID:30771478;PMID:27099744;PMID:25868664;PMID:23993194;PMID:32779419)
- Elevated circulating hepatic transaminase concentration (HP:0002910): Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage. Evidence: TAS. Frequency: Occasional (HP:0040283). (OMIM:615471)
- Cytochrome C oxidase-negative muscle fibers (HP:0003688): An abnormally reduced activity of the enzyme cytochrome C oxidase in muscle tissue. Evidence: PCS. Frequency: 1/1. (PMID:26404457)
- 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: 5/5. (PMID:27182039;PMID:26404457;PMID:31969900;PMID:32779419)
- Prominent supraorbital ridges (HP:0000336): Greater than average forward and/or lateral protrusion of the supraorbital portion of the frontal bones. Evidence: PCS. Frequency: 1/1. (PMID:30804983)
- Right ventricular hypertrophy (HP:0001667): In this case the right ventricle is more muscular than normal, causing a characteristic boot-shaped (coeur-en-sabot) appearance as seen on anterior- posterior chest x-rays. Right ventricular hypertrophy is commonly associated with any form of right ventricular outflow obstruction or pulmonary hypertension, which may in turn owe its origin to left-sided disease. The echocardiographic signs are thickening of the anterior right ventricular wall and the septum. Cavity size is usually normal, or slightly enlarged. In many cases there is associated volume overload present due to tricuspid regurgitation, in the absence of this, septal motion is normal. Evidence: PCS. Frequency: 2/9. (PMID:27743463)
- Decreased circulating immunoglobulin concentration (HP:0004313): An abnormally decreased level of immunoglobulin in blood. Evidence: PCS. Frequency: 1/1. (PMID:26404457)
- Dysphagia (HP:0002015): Difficulty in swallowing. Evidence: PCS. Frequency: 2/3. (PMID:30804983;PMID:31969900;PMID:32779419)
- Juvenile onset (HP:0003621): Onset of signs or symptoms of disease between the age of 5 and 15 years. Evidence: PCS. Frequency: 2/38. (PMID:27290639;PMID:28940506)
- Scoliosis (HP:0002650): The presence of an abnormal lateral curvature of the spine. Evidence: TAS. Frequency: Occasional (HP:0040283). (OMIM:615471)
- Cerebellar hypoplasia (HP:0001321): Cerebellar hypoplasia is a descriptive term implying a cerebellum with a reduced volume, but a normal shape and is stable over time. Evidence: PCS. Frequency: 1/1. (PMID:31442532)
- Everted lower lip vermilion (HP:0000232): An abnormal configuration of the lower lip such that it is turned outward i.e., everted, with the Inner aspect of the lower lip vermilion (normally opposing the teeth) being visible in a frontal view. Evidence: TAS. (OMIM:615471)
- 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: 3/5. (PMID:27182039;PMID:32559514;PMID:34602956;PMID:31969900;PMID:32779419)
- Prominent metopic ridge (HP:0005487): Vertical bony ridge positioned in the midline of the forehead. Evidence: PCS. Frequency: 2/2. (PMID:27182039;PMID:34602956)
- Bilateral tonic-clonic seizure with generalized onset (HP:0025190): A bilateral tonic-clonic seizure with generalized onset is a type of bilateral tonic-clonic seizure characterized by generalized onset; these seizures rapidly engage networks in both hemispheres at the start of the seizure. Evidence: PCS. Frequency: 8/37. (PMID:28940506;PMID:30771478;PMID:23993194)
- Pulmonary arterial hypertension (HP:0002092): Pulmonary hypertension is defined mean pulmonary artery pressure of 25mmHg or more and pulmonary capillary wedge pressure of 15mmHg or less when measured by right heart catheterisation at rest and in a supine position. Evidence: PCS. Frequency: 5/63. (PMID:28940506;PMID:27743463;PMID:26404457;PMID:25868664;PMID:27099744;PMID:23993194)
- Severe global developmental delay (HP:0011344): A severe delay in the achievement of motor or mental milestones in the domains of development of a child. Evidence: IEA. (OMIM:615471)
- 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: 5/66. (PMID:27290639;PMID:27182039;PMID:28940506;PMID:25868664;PMID:27099744;PMID:23993194)
- Left ventricular hypertrophy (HP:0001712): Enlargement or increased size of the heart left ventricle. Evidence: PCS. Frequency: 1/9. (PMID:27743463)
- 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: 18/36. (PMID:27290639;PMID:28940506;PMID:23993193;PMID:25868664;PMID:23993194)
- Frontal bossing (HP:0002007): Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline. Evidence: PCS. Frequency: 2/2. (PMID:30804983;PMID:32779419)
- Micrognathia (HP:0000347): Developmental hypoplasia of the mandible. Evidence: PCS. Frequency: 4/66. (PMID:27290639;PMID:28940506;PMID:25868664;PMID:27099744;PMID:23993194;PMID:32779419)
- Polymicrogyria (HP:0002126): Polymicrogyria is a congenital malformation of the cerebral cortex characterized by abnormal cortical layering (lamination) and an excessive number of small gyri (folds). Evidence: PCS. Frequency: 1/1. (PMID:31442532)
- Epicanthus (HP:0000286): A fold of skin starting above the medial aspect of the upper eyelid and arching downward to cover, pass in front of and lateral to the medial canthus. Evidence: PCS. Frequency: 11/67. (PMID:27290639;PMID:27182039;PMID:28940506;PMID:34602956;PMID:27099744;PMID:25868664;PMID:23993194)
- Delayed CNS myelination (HP:0002188): Delayed myelination in the central nervous system. Evidence: PCS. Frequency: 1/6. (PMID:23993193)
- Short foot (HP:0001773): A measured foot length that is more than 2 SD below the mean for a newborn of 27 - 41 weeks gestation, or foot that is less than the 3rd centile for individuals from birth to 16 years of age (objective). Alternatively, a foot that appears disproportionately short (subjective). Evidence: TAS. Frequency: Occasional (HP:0040283). (OMIM:615471)
- 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: 9/17. (PMID:28940506;PMID:27743463;PMID:25868664;PMID:27099744;PMID:23993194)
- 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: 20/26. (PMID:28940506;PMID:27182039;PMID:34602956;PMID:26404457;PMID:32779419)
- 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: 84/90. (PMID:27182039;PMID:32559514;PMID:28940506;PMID:23993193;PMID:32779419;PMID:23993194;PMID:34602956;PMID:27743463;PMID:30771478;PMID:30804983;PMID:26404457;PMID:31969900;PMID:25868664;PMID:27099744)
- 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: PCS. Frequency: 7/47. (PMID:27290639;PMID:28940506;PMID:25868664;PMID:23993194)
- Childhood onset (HP:0011463): Onset of disease at the age of between 1 and 5 years. Evidence: PCS. Frequency: 9/64. (PMID:28940506;PMID:27743463;PMID:25868664)
- Smooth philtrum (HP:0000319): Flat skin surface, with no ridge formation in the central region of the upper lip between the nasal base and upper vermilion border. Evidence: PCS. Frequency: 10/70. (PMID:27290639;PMID:28940506;PMID:27182039;PMID:30804983;PMID:34602956;PMID:26404457;PMID:27099744;PMID:25868664;PMID:23993194;PMID:32779419)
- Prominent forehead (HP:0011220): Forward prominence of the entire forehead, due to protrusion of the frontal bone. Evidence: PCS. Frequency: 14/67. (PMID:27290639;PMID:27182039;PMID:28940506;PMID:34602956;PMID:27099744;PMID:25868664;PMID:23993194)
- Hypertelorism (HP:0000316): Interpupillary distance more than 2 SD above the mean (alternatively, the appearance of an increased interpupillary distance or widely spaced eyes). Evidence: PCS. Frequency: 8/66. (PMID:27290639;PMID:28940506;PMID:32559514;PMID:27099744;PMID:25868664;PMID:23993194)
- Decreased total lymphocyte count (HP:0001888): A reduced number of lymphocytes in the blood. Evidence: PCS. Frequency: 1/1. (PMID:26404457)
- CNS hypomyelination (HP:0003429): Reduced amount of myelin in the central nervous system resulting from defective myelinogenesis. Evidence: PCS. Frequency: 2/2. (PMID:27182039;PMID:26404457)
- Patent ductus arteriosus (HP:0001643): In utero, the ductus arteriosus (DA) serves to divert ventricular output away from the lungs and toward the placenta by connecting the main pulmonary artery to the descending aorta. A patent ductus arteriosus (PDA) in the first 3 days of life is a physiologic shunt in healthy term and preterm newborn infants, and normally is substantially closed within about 24 hours after bith and completely closed after about three weeks. Failure of physiologcal closure is referred to a persistent or patent ductus arteriosus (PDA). Depending on the degree of left-to-right shunting, PDA can have clinical consequences. Evidence: PCS. Frequency: 5/11. (PMID:28940506;PMID:27743463)
- Supraventricular tachycardia (HP:0004755): Supraventricular tachycardia (SVT) is an abnormally increased heart rate (over 100 beats per minute at rest) with origin above the level of the ventricles. Evidence: PCS. Frequency: 3/46. (PMID:28940506;PMID:27743463)
- Periventricular cysts (HP:0007109). Evidence: PCS. Frequency: 6/48. (PMID:28940506;PMID:25868664;PMID:27099744;PMID:23993194)
- Skeletal muscle atrophy (HP:0003202): The presence of skeletal muscular atrophy (which is also known as amyotrophy). Evidence: TAS. (OMIM:615471)
- Thick eyebrow (HP:0000574): Increased density/number and/or increased diameter of eyebrow hairs. Evidence: PCS. Frequency: 11/68. (PMID:27290639;PMID:28940506;PMID:27182039;PMID:30804983;PMID:34602956;PMID:25868664;PMID:27099744;PMID:23993194)
- Choreoathetosis (HP:0001266): Involuntary movements characterized by both athetosis (inability to sustain muscles in a fixed position) and chorea (widespread jerky arrhythmic movements). Evidence: TAS. Frequency: Occasional (HP:0040283). (OMIM:615471)
- Hypoplasia of the corpus callosum (HP:0002079): Underdevelopment of the corpus callosum. Evidence: TAS. (OMIM:615471)
- Short chin (HP:0000331): Decreased vertical distance from the vermilion border of the lower lip to the inferior-most point of the chin. Evidence: PCS. Frequency: 2/2. (PMID:27182039;PMID:34602956)
- 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: 36/51. (PMID:28940506;PMID:32559514;PMID:27182039;PMID:30804983;PMID:34602956;PMID:26404457;PMID:25868664;PMID:23993194;PMID:32779419)
- 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: 58/59. (PMID:32559514;PMID:27182039;PMID:28940506;PMID:23993193;PMID:27743463;PMID:30771478;PMID:31442532;PMID:31969900;PMID:32779419)
- Umbilical hernia (HP:0001537): Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect. Evidence: PCS. Frequency: 1/1. (PMID:27182039)
- Hypospadias (HP:0000047): Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum. Evidence: PCS. Frequency: 8/44. (PMID:27182039;PMID:28940506;PMID:31969900;PMID:27099744;PMID:25868664;PMID:23993194)
- Patent foramen ovale (HP:0001655): Failure of the foramen ovale to seal postnatally, leaving a potential conduit between the left and right cardiac atria. Evidence: PCS. Frequency: 7/46. (PMID:28940506;PMID:27743463)
- Inguinal hernia (HP:0000023): Protrusion of the contents of the abdominal cavity through the inguinal canal. Evidence: PCS. Frequency: 1/1. (PMID:34602956)
- Antenatal onset (HP:0030674): Onset prior to birth. Evidence: PCS. Frequency: 3/11. (PMID:30771478;PMID:27743463;PMID:34602956)
- Global brain atrophy (HP:0002283): Unlocalized atrophy of the brain with decreased total brain matter volume and increased ventricular size. Evidence: PCS. Frequency: 39/39. (PMID:27290639;PMID:27182039;PMID:30804983;PMID:27099744;PMID:25868664;PMID:23993194)
- Arrhythmia (HP:0011675): Any cardiac rhythm other than the normal sinus rhythm. Such a rhythm may be either of sinus or ectopic origin and either regular or irregular. An arrhythmia may be due to a disturbance in impulse formation or conduction or both. Evidence: TAS. Frequency: Occasional (HP:0040283). (OMIM:615471)
- Enlarged cisterna magna (HP:0002280): Increase in size of the cisterna magna, one of three principal openings in the subarachnoid space between the arachnoid and pia mater, located between the cerebellum and the dorsal surface of the medulla oblongata. Evidence: PCS. Frequency: 13/49. (PMID:28940506;PMID:27099744;PMID:25868664;PMID:31969900;PMID:23993194)
- Failure to thrive (HP:0001508): Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm. Evidence: PCS. Frequency: 32/55. (PMID:28940506;PMID:30804983;PMID:27743463;PMID:26404457;PMID:25868664;PMID:23993194)
- Recurrent infections (HP:0002719): Increased susceptibility to infections as manifested by repeated bouts of infection. Evidence: PCS. Frequency: 10/37. (PMID:28940506)
- Anemia (HP:0001903): A reduction in erythrocytes volume or hemoglobin concentration. Evidence: PCS. Frequency: 2/2. (PMID:30804983;PMID:32779419)
- Hyperammonemia (HP:0001987): An increased concentration of ammonia in the blood. Evidence: PCS. Frequency: 26/58. (PMID:28940506;PMID:32559514;PMID:23993193;PMID:30771478;PMID:30804983;PMID:27743463;PMID:27099744;PMID:25868664;PMID:31969900;PMID:23993194;PMID:32779419)
- Decreased activity of mitochondrial complex II (HP:0008314): A reduction in the activity of the mitochondrial respiratory chain complex II, which is part of the electron transport chain in mitochondria. Evidence: PCS. Frequency: 12/35. (PMID:27290639;PMID:28940506;PMID:25868664;PMID:23993194)
- Lacticaciduria (HP:0003648): An increased concentration of lactic acid in the urine. Evidence: PCS. Frequency: 5/5. (PMID:27182039;PMID:32559514;PMID:34602956;PMID:30771478;PMID:26404457)
- Protruding ear (HP:0000411): Angle formed by the plane of the ear and the mastoid bone greater than the 97th centile for age (objective); or, outer edge of the helix more than 2 cm from the mastoid at the point of maximum distance (objective). Evidence: TAS. (OMIM:615471)
- Hyperreflexia (HP:0001347): Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles. Evidence: PCS. Frequency: 1/1. (PMID:27182039)
- 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: 7/7. (PMID:23993193)
- Premature birth (HP:0001622): The birth of a baby of less than 37 weeks of gestational age. Evidence: PCS. Frequency: 7/52. (PMID:27290639;PMID:28940506;PMID:27099744;PMID:25868664;PMID:23993194)
- Narrow face (HP:0000275): Bizygomatic (upper face) and bigonial (lower face) width are both more than 2 standard deviations below the mean (objective); or, an apparent reduction in the width of the upper and lower face (subjective). Evidence: TAS. (OMIM:615471)
- Cerebral atrophy (HP:0002059): Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum. Evidence: PCS. Frequency: 32/62. (PMID:27182039;PMID:28940506;PMID:23993193;PMID:27743463;PMID:34602956;PMID:25868664;PMID:27099744;PMID:32779419;PMID:23993194)
- Wide nasal bridge (HP:0000431): Increased breadth of the nasal bridge (and with it, the nasal root). Evidence: PCS. Frequency: 15/68. (PMID:27290639;PMID:28940506;PMID:27182039;PMID:32559514;PMID:34602956;PMID:25868664;PMID:27099744;PMID:23993194)
- Enlarged fetal cisterna magna (HP:0011427): The cisterna magna is measured on a transaxial view of the fetal head angled 15 degrees caudal to the canthomeatal line. The anterior/posterior diameter is taken between the inferior/posterior surface of the vermis of the cerebellum to the inner surface of the cranium. An enlarged cisternal magna is defined by an anterior/posterior diameter of 10 mm or more (PMID:16100637). Evidence: PCS. Frequency: 1/1. (PMID:31969900)
- Elevated urine fumaric acid level (HP:0034648): The concentration of fumaric acid in the urine, normalized for urine concentration, is above the upper limit of normal. Evidence: PCS. Frequency: 1/1. (PMID:32779419)
- Hypertrophic cardiomyopathy (HP:0001639): Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality. Evidence: PCS. Frequency: 15/56. (PMID:28940506;PMID:34602956;PMID:31442532;PMID:27099744;PMID:25868664;PMID:23993194)
- 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: 28/44. (PMID:27290639;PMID:28940506;PMID:27099744;PMID:25868664;PMID:23993194)
- Tetralogy of Fallot (HP:0001636): A congenital cardiac malformation comprising pulmonary stenosis, overriding aorta, ventricular septum defect, and right ventricular hypertrophy. The diagnosis of TOF is made if at least three of the four above mentioned features are present. Evidence: PCS. Frequency: 1/46. (PMID:28940506;PMID:27743463)
- Plagiocephaly (HP:0001357): Asymmetric head shape, which is usually a combination of unilateral occipital flattening with ipsilateral frontal prominence, leading to rhomboid cranial shape. Evidence: TAS. Frequency: Occasional (HP:0040283). (OMIM:615471)
- Synophrys (HP:0000664): Meeting of the medial eyebrows in the midline. Evidence: PCS. Frequency: 4/28. (PMID:27290639;PMID:25868664;PMID:27099744;PMID:23993194)
- Atrial septal defect (HP:0001631): Atrial septal defect (ASD) is a congenital abnormality of the interatrial septum that enables blood flow between the left and right atria via the interatrial septum. Evidence: PCS. Frequency: 4/19. (PMID:28940506;PMID:27743463;PMID:25868664;PMID:27099744;PMID:23993194)
- Growth delay (HP:0001510): A deficiency or slowing down of growth pre- and postnatally. Evidence: TAS. (OMIM:615471)
- Cryptorchidism (HP:0000028): Testis in inguinal canal. That is, absence of one or both testes from the scrotum owing to failure of the testis or testes to descend through the inguinal canal to the scrotum. Evidence: PCS. Frequency: 11/46. (PMID:28940506;PMID:27182039;PMID:34602956;PMID:31442532;PMID:25868664;PMID:27099744;PMID:31969900;PMID:23993194)
- 3-Methylglutaconic aciduria (HP:0003535): An increased amount of 3-methylglutaconic acid in the urine. Evidence: PCS. Frequency: 1/1. (PMID:31442532)
- Decreased total neutrophil count (HP:0001875): Abnormal decrease of absolute number of neutrophils in the blood, per microlitre, compared to a reference range for a given sex and age-group. Evidence: PCS. Frequency: 13/70. (PMID:28940506;PMID:26404457;PMID:25868664;PMID:27099744;PMID:23993194;PMID:32779419)