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Intellectual disability, autosomal recessive 53(NEDHSCA)

MedGen UID:: 934761
•Concept ID:: C4310794
•: Disease or Syndrome

Synonyms:	GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 13; Mental retardation, autosomal recessive 53; NEDHSCA; NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT HYPOTONIA, SEIZURES, AND CEREBELLAR ATROPHY

Gene (location): Gene(s) directly associated with this condition or phenotype.	PIGG (4p16.3)

Monarch Initiative:	MONDO:0014832
OMIM®:	616917
Orphanet:	ORPHA488635

Definition

Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy (NEDHSCA) is an autosomal recessive disorder characterized by severely delayed psychomotor development, hypotonia apparent since infancy, and early-onset seizures in most patients. Some patients may have additional features, such as cerebellar atrophy, ataxia, and nonspecific dysmorphic features. NEDHSCA is one of a group of similar neurologic disorders resulting from biochemical defects in the glycosylphosphatidylinositol (GPI) biosynthetic pathway. Some patients with NEDHSCA may have the Emm-null blood group phenotype (see 619812) (summary by Makrythanasis et al., 2016; Duval et al., 2021). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293). [from OMIM]

Clinical features

From HPO

Fetal growth restriction

MedGen UID:: 4693
•Concept ID:: C0015934
•: Pathologic Function

An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.

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Cerebellar ataxia

MedGen UID:: 849
•Concept ID:: C0007758
•: 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).

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Seizure

MedGen UID:: 20693
•Concept ID:: C0036572
•: Sign or Symptom

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.

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Cerebral atrophy

MedGen UID:: 116012
•Concept ID:: C0235946
•: Disease or Syndrome

Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.

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Cerebellar hypoplasia

MedGen UID:: 120578
•Concept ID:: C0266470
•: Congenital Abnormality

Cerebellar hypoplasia is a descriptive term implying a cerebellum with a reduced volume, but a normal shape and is stable over time.

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Hypoplasia of the corpus callosum

MedGen UID:: 138005
•Concept ID:: C0344482
•: Congenital Abnormality

Underdevelopment of the corpus callosum.

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Delayed speech and language development

MedGen UID:: 105318
•Concept ID:: C0454644
•: Finding

A degree of language development that is significantly below the norm for a child of a specified age.

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Global developmental delay

MedGen UID:: 107838
•Concept ID:: C0557874
•: Finding

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.

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Hyporeflexia

MedGen UID:: 195967
•Concept ID:: C0700078
•: Finding

Reduction of neurologic reflexes such as the knee-jerk reaction.

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Absent speech

MedGen UID:: 340737
•Concept ID:: C1854882
•: Finding

Complete lack of development of speech and language abilities.

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Intellectual disability, profound

MedGen UID:: 892508
•Concept ID:: C3161330
•: Mental or Behavioral Dysfunction

Profound mental retardation is defined as an intelligence quotient (IQ) below 20.

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EEG with focal spikes

MedGen UID:: 869063
•Concept ID:: C4023481
•: Finding

EEG with focal sharp transient waves of a duration less than 80 msec.

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Severe muscular hypotonia

MedGen UID:: 326544
•Concept ID:: C1839630
•: Finding

A severe degree of muscular hypotonia characterized by markedly reduced muscle tone.

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Generalized hypotonia

MedGen UID:: 346841
•Concept ID:: C1858120
•: Finding

Generalized muscular hypotonia (abnormally low muscle tone).

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Elevated circulating alkaline phosphatase concentration

MedGen UID:: 727252
•Concept ID:: C1314665
•: Finding

Abnormally increased serum levels of alkaline phosphatase activity.

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Abnormality of metabolism/homeostasis
- Elevated circulating alkaline phosphatase concentration
Abnormality of the musculoskeletal system
- Generalized hypotonia
- Severe muscular hypotonia
Abnormality of the nervous system
Growth abnormality
- Fetal growth restriction

Term Hierarchy

GTR
MeSH

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVIntellectual disability, autosomal recessive 53

Congenital disorder of glycosylation with epilepsy as a major feature
- Intellectual disability, autosomal recessive 53

Professional guidelines

PubMed

Evaluation of patients diagnosed with phenylketonuria and biotinidase deficiency by the newborn screening program: a ten-year retrospective study.

Toktaş İ, Sarıbaş S, Canpolat S, Erdem Ö, Özbek MN
Turk J Pediatr 2022;64(6):985-992. doi: 10.24953/turkjped.2022.467. PMID: 36583880

Assessing Utility of Clinical Exome Sequencing in Diagnosis of Rare Idiopathic Neurodevelopmental Disorders in Indian Population.

Sheth H, Pancholi D, Bhavsar R, Mannan AU, Ganapathy A, Chowdhury M, Shah S, Solanki D, Sheth F, Sheth J
Neurol India 2021 Nov-Dec;69(6):1729-1736. doi: 10.4103/0028-3886.333475. PMID: 34979677

Clinical utility of exome sequencing in individuals with large homozygous regions detected by chromosomal microarray analysis.

Prasad A, Sdano MA, Vanzo RJ, Mowery-Rushton PA, Serrano MA, Hensel CH, Wassman ER
BMC Med Genet 2018 Mar 20;19(1):46. doi: 10.1186/s12881-018-0555-3. PMID: 29554876 Free PMC Article

See all (3)

Recent clinical studies

Etiology

Evaluation of patients diagnosed with phenylketonuria and biotinidase deficiency by the newborn screening program: a ten-year retrospective study.

Toktaş İ, Sarıbaş S, Canpolat S, Erdem Ö, Özbek MN
Turk J Pediatr 2022;64(6):985-992. doi: 10.24953/turkjped.2022.467. PMID: 36583880

Patterns of neurological manifestations in Woodhouse-Sakati Syndrome.

Bohlega S, Abusrair AH, Al-Ajlan FS, Alharbi N, Al-Semari A, Bohlega B, Abualsaud D, Alkuraya F
Parkinsonism Relat Disord 2019 Dec;69:99-103. Epub 2019 Oct 13 doi: 10.1016/j.parkreldis.2019.10.007. PMID: 31726291

Identification and functional characterization of two novel mutations in KCNJ10 and PI4KB in SeSAME syndrome without electrolyte imbalance.

Nadella RK, Chellappa A, Subramaniam AG, More RP, Shetty S, Prakash S, Ratna N, Vandana VP, Purushottam M, Saini J, Viswanath B, Bindu PS, Nagappa M, Mehta B, Jain S, Kannan R
Hum Genomics 2019 Oct 22;13(1):53. doi: 10.1186/s40246-019-0236-0. PMID: 31640787 Free PMC Article

Clinical utility of exome sequencing in individuals with large homozygous regions detected by chromosomal microarray analysis.

Prasad A, Sdano MA, Vanzo RJ, Mowery-Rushton PA, Serrano MA, Hensel CH, Wassman ER
BMC Med Genet 2018 Mar 20;19(1):46. doi: 10.1186/s12881-018-0555-3. PMID: 29554876 Free PMC Article

Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum.

Smogavec M, Cleall A, Hoyer J, Lederer D, Nassogne MC, Palmer EE, Deprez M, Benoit V, Maystadt I, Noakes C, Leal A, Shaw M, Gecz J, Raymond L, Reis A, Shears D, Brockmann K, Zweier C
J Med Genet 2016 Dec;53(12):820-827. Epub 2016 Jul 20 doi: 10.1136/jmedgenet-2016-103880. PMID: 27439707

See all (7)

Diagnosis

Evaluation of patients diagnosed with phenylketonuria and biotinidase deficiency by the newborn screening program: a ten-year retrospective study.

Toktaş İ, Sarıbaş S, Canpolat S, Erdem Ö, Özbek MN
Turk J Pediatr 2022;64(6):985-992. doi: 10.24953/turkjped.2022.467. PMID: 36583880

Detecting regions of homozygosity improves the diagnosis of pathogenic variants and uniparental disomy in pediatric patients.

Wen J, Chai H, Grommisch B, DiAdamo A, Dykas D, Ma D, Popa A, Zhao C, Spencer-Manzon M, Jiang YH, McGrath J, Li P, Bale A, Zhang H
Am J Med Genet A 2022 Jun;188(6):1728-1738. Epub 2022 Feb 23 doi: 10.1002/ajmg.a.62693. PMID: 35199448

Assessing Utility of Clinical Exome Sequencing in Diagnosis of Rare Idiopathic Neurodevelopmental Disorders in Indian Population.

Sheth H, Pancholi D, Bhavsar R, Mannan AU, Ganapathy A, Chowdhury M, Shah S, Solanki D, Sheth F, Sheth J
Neurol India 2021 Nov-Dec;69(6):1729-1736. doi: 10.4103/0028-3886.333475. PMID: 34979677

Patterns of neurological manifestations in Woodhouse-Sakati Syndrome.

Diagnostic exome sequencing in persons with severe intellectual disability.

de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE
N Engl J Med 2012 Nov 15;367(20):1921-9. Epub 2012 Oct 3 doi: 10.1056/NEJMoa1206524. PMID: 23033978

See all (16)

Therapy

Case study for the evaluation of current treatment recommendations of guanidinoacetate methyltransferase deficiency: ineffectiveness of sodium benzoate.

Mercimek-Mahmutoglu S, Salomons GS, Chan A
Pediatr Neurol 2014 Jul;51(1):133-7. Epub 2014 Feb 21 doi: 10.1016/j.pediatrneurol.2014.02.011. PMID: 24766785

See all (1)

Prognosis

Detecting regions of homozygosity improves the diagnosis of pathogenic variants and uniparental disomy in pediatric patients.

Patterns of neurological manifestations in Woodhouse-Sakati Syndrome.

Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum.

Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family.

Rafiullah R, Aslamkhan M, Paramasivam N, Thiel C, Mustafa G, Wiemann S, Schlesner M, Wade RC, Rappold GA, Berkel S
J Med Genet 2016 Feb;53(2):138-44. Epub 2015 Nov 13 doi: 10.1136/jmedgenet-2015-103179. PMID: 26566883

Diagnostic exome sequencing in persons with severe intellectual disability.

See all (8)