- Premature closure of fontanelles (HP:0005458): Normally, the posterior and lateral fontanelles are obliterated by about six months after birth, the anterior fontanelle closes by about the middle of the second year. This term refers to the situation in which the fontanelles close at an inappropriately early time point. Evidence: IEA. (OMIM:610127)
- Congenital onset (HP:0003577): A phenotypic abnormality that is present at birth. Evidence: PCS. Frequency: 4/4. (PMID:16670177)
- Sloping forehead (HP:0000340): Inclination of the anterior surface of the forehead from the vertical more than two standard deviations above the mean (objective); or apparently excessive posterior sloping of the forehead in a lateral view. Evidence: PCS. Frequency: 1/4. (PMID:16670177)
- 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: 6/6. (PMID:25298308;PMID:16685649)
- 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: 3/4. (PMID:16670177)
- Rigidity (HP:0002063): Continuous involuntary sustained muscle contraction. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity. Evidence: IEA. (OMIM:610127)
- 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: 6/6. (PMID:25298308;PMID:16685649)
- Myoclonic seizure (HP:0032794): A myoclonic seizure is a type of motor seizure characterized by sudden, brief (<100 ms) involuntary single or multiple contraction of muscles or muscle groups of variable topography (axial, proximal limb, distal). Myoclonus is less regularly repetitive and less sustained than is clonus. Evidence: PCS. Frequency: 1/4. Onset: Fetal onset (HP:0011461). (PMID:16670177)
- Sensory axonal neuropathy (HP:0003390): An axonal neuropathy of peripheral sensory nerves. Evidence: PCS. Frequency: 2/5. (PMID:25298308)
- Split hand (HP:0001171): A condition in which middle parts of the hand (fingers and metacarpals) are missing giving a cleft appearance. The severity is very variable ranging from slightly hypoplastic middle fingers over absent middle fingers as far as oligo- or monodactyl hands. Evidence: PCS. Frequency: 1/4. (PMID:16670177)
- 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: 1/1. (PMID:16685649)
- Childhood onset (HP:0011463): Onset of disease at the age of between 1 and 5 years. Evidence: PCS. Frequency: 1/1. (PMID:16685649)
- Respiratory failure (HP:0002878): A severe form of respiratory insufficiency characterized by inadequate gas exchange such that the levels of oxygen or carbon dioxide cannot be maintained within normal limits. Evidence: PCS. Frequency: 1/4. (PMID:16670177)
- Rod-cone dystrophy (HP:0000510): An inherited retinal disease subtype in which the rod photoreceptors appear to be more severely affected than the cone photoreceptors. Typical presentation is with nyctalopia (due to rod dysfunction) followed by loss of mid-peripheral field of vision, which gradually extends and leaves many patients with a small central island of vision due to the preservation of macular cones. Evidence: PCS. Frequency: 5/5. (PMID:25298308)
- Mental deterioration (HP:0001268): Loss of previously present mental abilities, generally in adults. Evidence: PCS. Frequency: 6/6. (PMID:25298308;PMID:16685649)
- 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: IEA. (OMIM:610127)
- Retinal atrophy (HP:0001105): A nonspecific term denoting wasting, especially as a result of degeneration, of the retinal pigment epithelium (RPE) and neurosensory retinal cells. Evidence: PCS. Frequency: 1/1. (PMID:16685649)
- Visual loss (HP:0000572): Loss of visual acuity (implying that vision was better at a certain time point in life). Otherwise the term reduced visual acuity should be used (or a subclass of that). Evidence: TAS. (OMIM:610127)
- Cerebral atrophy (HP:0002059): Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum. Evidence: PCS. Frequency: 1/1. (PMID:16685649)
- Microcephaly (HP:0000252): Head circumference below 2 standard deviations below the mean for age and gender. Evidence: PCS. Frequency: 3/4. (PMID:16670177)
- Status epilepticus (HP:0002133): Status epilepticus is a type of prolonged seizure resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures (after time point t1). It is a condition that can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. Evidence: IEA. (OMIM:610127)
- Wide nasal bridge (HP:0000431): Increased breadth of the nasal bridge (and with it, the nasal root). Evidence: PCS. Frequency: 1/4. (PMID:16670177)
- Increased neuronal autofluorescent lipopigment (HP:0002074): Lipofuscin, a generic term applied to autofluorescent lipopigment, is a mixture of protein and lipid that accumulates in most aging cells, particularly those involved in high lipid turnover (e.g., the adrenal medulla) or phagocytosis of other cell types (e g., the retinal pigment epithelium or RPE; macrophage). This term pertains if there is an increase in the neuronal accumulation of lipofuscin (also known as autofluorescent lipoprotein) more than expected for the age of the patient. Evidence: IEA. (OMIM:610127)
- Respiratory insufficiency (HP:0002093). Evidence: IEA. (OMIM:610127)
- 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:16685649)
- Neuronal loss in central nervous system (HP:0002529). Evidence: TAS. (OMIM:610127)
- Neonatal death (HP:0003811): Death within the first 28 days of life. Evidence: PCS. Frequency: 1/4. (PMID:16670177)
- Vascular granular osmiophilic material deposition (HP:0003657): Accumulation of granular osmiophilic material in blood vessel walls. Osmiophilic material becomes black upon staining with osmium tetroxide. Deposition of granular osmiophilic material (GOM) is the vascular pathological hallmark of CADASIL, which is the most prevalent hereditary small vessel disease and is caused by missense mutations in the NOTCH3 gene. GOM have been shown to contain NOTCH3 ectodomain (NOTCH3ECD) and extracellular matrix proteins, and can be visualized ultrastructurally in the tunica media of small arteries and capillaries. These electron dense GOM deposits are located in the basement membrane of mural cells, i.e. vascular smooth muscle cells and pericytes. In both manifest and pre-manifest CADASIL patients, GOM deposits are present not only in brain vessels, but also in vessels of other organs, such as the skin. Evidence: PCS. Frequency: 2/5. (PMID:25298308)
- Spasticity (HP:0001257): A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes. Evidence: PCS. Frequency: 3/4. (PMID:16670177)
- Apnea (HP:0002104): Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event. Evidence: PCS. Frequency: 4/4. (PMID:16670177)
- 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: 3/4. (PMID:16670177)
These phenotypes are associated with the disease neuronal ceroid lipofuscinosis 10 (OMIM:610127).