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Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures(NEDHCAS; GPIBD22)

MedGen UID:
Concept ID:
Disease or Syndrome
Gene (location): PIGK (1p31.1)
Monarch Initiative: MONDO:0030037
OMIM®: 618879


Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures (NEDHCAS) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay with variably impaired intellectual development, delayed motor skills, and poor or absent speech. Most patients develop early-onset seizures and demonstrate cerebellar ataxia or dysmetria associated with progressive cerebellar atrophy on brain imaging. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis (summary by Nguyen et al., 2020). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293). [from OMIM]

Clinical features

From HPO
MedGen UID:
Concept ID:
Congenital Abnormality
Digits that appear disproportionately short compared to the hand/foot. The word brachydactyly is used here to describe a series distinct patterns of shortened digits (brachydactyly types A-E). This is the sense used here.
Prominent antitragus
MedGen UID:
Concept ID:
Increased anterosuperior prominence of the area between the bottom of the incisura and the inner margin of the antihelix.
Cerebellar ataxia
MedGen UID:
Concept ID:
Disease or Syndrome
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).
MedGen UID:
Concept ID:
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Global developmental delay
MedGen UID:
Concept ID:
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.
Cerebellar atrophy
MedGen UID:
Concept ID:
Disease or Syndrome
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.
Generalized hypotonia
MedGen UID:
Concept ID:
Generalized muscular hypotonia (abnormally low muscle tone).
Low alkaline phosphatase
MedGen UID:
Concept ID:
Abnormally reduced serum levels of alkaline phosphatase.
Dental crowding
MedGen UID:
Concept ID:
Changes in alignment of teeth in the dental arch
Long face
MedGen UID:
Concept ID:
Facial height (length) is more than 2 standard deviations above the mean (objective); or, an apparent increase in the height (length) of the face (subjective).
Prominent forehead
MedGen UID:
Concept ID:
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Sparse lateral eyebrow
MedGen UID:
Concept ID:
Decreased density/number and/or decreased diameter of lateral eyebrow hairs.
Thin upper lip vermilion
MedGen UID:
Concept ID:
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).
High anterior hairline
MedGen UID:
Concept ID:
Distance between the hairline (trichion) and the glabella (the most prominent point on the frontal bone above the root of the nose), in the midline, more than two SD above the mean. Alternatively, an apparently increased distance between the hairline and the glabella.
Decreased expression of GPI-anchored proteins on the cell surface
MedGen UID:
Concept ID:
A decrease in the protein expression fo GPI-anchor proteins, such as CD55 and CD59, at the cell surface, which suggests a defect in GPI-anchor biosynthesis.

Professional guidelines


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Ziobro J, Shellhaas RA
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Recent clinical studies


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Shellhaas RA
Handb Clin Neurol 2019;162:347-361. doi: 10.1016/B978-0-444-64029-1.00017-5. PMID: 31324320
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Clinical prediction guides

Hunt RW, Liley HG, Wagh D, Schembri R, Lee KJ, Shearman AD, Francis-Pester S, deWaal K, Cheong JYL, Olischar M, Badawi N, Wong FY, Osborn DA, Rajadurai VS, Dargaville PA, Headley B, Wright I, Colditz PB; Newborn Electrographic Seizure Trial Investigators
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Recent systematic reviews

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