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Intellectual disability, autosomal recessive 42(NEDDSBA)

MedGen UID:
862780
Concept ID:
C4014343
Disease or Syndrome
Synonyms: GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 9; NEDDSBA; Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities
 
Gene (location): PGAP1 (2q33.1)
 
Monarch Initiative: MONDO:0014348
OMIM®: 615802

Definition

Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities (NEDDSBA) is an autosomal recessive neurodevelopmental disorder characterized by severely delayed global development, with hypotonia, impaired intellectual development, and poor or absent speech. Most patients have spasticity with limb hypertonia and brisk tendon reflexes. Additional features include nonspecific dysmorphic facial features, structural brain abnormalities, and cortical visual impairment (summary by Bosch et al., 2015). Novarino et al. (2014) labeled the disorder 'spastic paraplegia-67' (SPG67). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293). [from OMIM]

Clinical features

From HPO
Atrial septal defect, ostium secundum type
MedGen UID:
91034
Concept ID:
C0344724
Congenital Abnormality
A kind of atrial septum defect arising from an enlarged foramen ovale, inadequate growth of the septum secundum, or excessive absorption of the septum primum.
Pulmonic stenosis
MedGen UID:
408291
Concept ID:
C1956257
Disease or Syndrome
A narrowing of the right ventricular outflow tract that can occur at the pulmonary valve (valvular stenosis), below the pulmonary valve (infundibular stenosis), or above the pulmonary valve (supravalvar stenosis).
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
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).
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Gastrostomy tube feeding in infancy
MedGen UID:
892362
Concept ID:
C4023342
Finding
Feeding problem necessitating gastrostomy tube feeding.
Macrotia
MedGen UID:
488785
Concept ID:
C0152421
Congenital Abnormality
Median longitudinal ear length greater than two standard deviations above the mean and median ear width greater than two standard deviations above the mean (objective); or, apparent increase in length and width of the pinna (subjective).
Prominent antihelix
MedGen UID:
335147
Concept ID:
C1845272
Finding
The presence of an abnormally prominent antihelix.
Dyskinesia
MedGen UID:
8514
Concept ID:
C0013384
Disease or Syndrome
A movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements.
Intellectual disability, moderate
MedGen UID:
7680
Concept ID:
C0026351
Mental or Behavioral Dysfunction
Moderate mental retardation is defined as an intelligence quotient (IQ) in the range of 35-49.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
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.
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.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
Motor stereotypies
MedGen UID:
21318
Concept ID:
C0038271
Individual Behavior
Use of the same abnormal action in response to certain triggers or at random. They may be used as a way to regulate one's internal state but must otherwise have no apparent functional purpose.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Corpus callosum, agenesis of
MedGen UID:
104498
Concept ID:
C0175754
Congenital Abnormality
The corpus callosum is the largest fiber tract in the central nervous system and the major interhemispheric fiber bundle in the brain. Formation of the corpus callosum begins as early as 6 weeks' gestation, with the first fibers crossing the midline at 11 to 12 weeks' gestation, and completion of the basic shape by age 18 to 20 weeks (Schell-Apacik et al., 2008). Agenesis of the corpus callosum (ACC) is one of the most frequent malformations in brain with a reported incidence ranging between 0.5 and 70 in 10,000 births. ACC is a clinically and genetically heterogeneous condition, which can be observed either as an isolated condition or as a manifestation in the context of a congenital syndrome (see MOLECULAR GENETICS and Dobyns, 1996). Also see mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600). Schell-Apacik et al. (2008) noted that there is confusion in the literature regarding radiologic terminology concerning partial absence of the corpus callosum, where various designations have been used, including hypogenesis, hypoplasia, partial agenesis, or dysgenesis.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Delayed ability to walk
MedGen UID:
66034
Concept ID:
C0241726
Finding
A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Inappropriate laughter
MedGen UID:
98407
Concept ID:
C0424304
Finding
Laughing that may be excessive and/or inappropriate in context (e.g., laughing at a funeral while others are crying).
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.
Bilateral tonic-clonic seizure
MedGen UID:
141670
Concept ID:
C0494475
Sign or Symptom
A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.
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.
Cerebellar vermis hypoplasia
MedGen UID:
333548
Concept ID:
C1840379
Finding
Underdevelopment of the vermis of cerebellum.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Enlarged sylvian cistern
MedGen UID:
866575
Concept ID:
C4020921
Finding
An increase in size of the subarachnoid space associated with the lateral cerebral sulcus (Sylvian fissure).
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Generalized non-motor (absence) seizure
MedGen UID:
1385688
Concept ID:
C4316903
Disease or Syndrome
A generalized non-motor (absence) seizure is a type of a type of dialeptic seizure that is of electrographically generalized onset. It is a generalized seizure characterized by an interruption of activities, a blank stare, and usually the person will be unresponsive when spoken to. Any ictal motor phenomena are minor in comparison to these non-motor features.
Delayed ability to sit
MedGen UID:
1368737
Concept ID:
C4476710
Finding
A failure to achieve the ability to sit at an appropriate developmental stage. Most children sit with support at 6 months of age and sit steadily without support at 9 months of age.
Delayed ability to roll over
MedGen UID:
1718874
Concept ID:
C5397980
Finding
Delayed achievement of the ability to roll front to back and back to front.
Delayed ability to crawl
MedGen UID:
1772845
Concept ID:
C5421628
Finding
A failure to achieve the ability to crawl at an appropriate developmental stage. Normal infant motor development is marked by a series of postural milestones including learning to crawl on hands and knees between the ages of 6 and 10 months.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
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.
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Neonatal hypotonia
MedGen UID:
412209
Concept ID:
C2267233
Disease or Syndrome
Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Enamel hypoplasia
MedGen UID:
3730
Concept ID:
C0011351
Disease or Syndrome
Developmental hypoplasia of the dental enamel.
Wide mouth
MedGen UID:
44238
Concept ID:
C0024433
Congenital Abnormality
Distance between the oral commissures more than 2 SD above the mean. Alternatively, an apparently increased width of the oral aperture (subjective).
Abnormality of the dentition
MedGen UID:
78084
Concept ID:
C0262444
Finding
Any abnormality of the teeth.
Upslanted palpebral fissure
MedGen UID:
98390
Concept ID:
C0423109
Finding
The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Low anterior hairline
MedGen UID:
331280
Concept ID:
C1842366
Finding
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 below the mean. Alternatively, an apparently decreased distance between the hairline and the glabella.
Low posterior hairline
MedGen UID:
383755
Concept ID:
C1855728
Finding
Hair on the neck extends more inferiorly than usual.
Highly arched eyebrow
MedGen UID:
358357
Concept ID:
C1868571
Finding
Increased height of the central portion of the eyebrow, forming a crescent, semicircular, or inverted U shape.
Bifid uvula
MedGen UID:
1646931
Concept ID:
C4551488
Congenital Abnormality
Uvula separated into two parts most easily seen at the tip.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Deeply set eye
MedGen UID:
473112
Concept ID:
C0423224
Finding
An eye that is more deeply recessed into the plane of the face than is typical.
Congenital nystagmus
MedGen UID:
195995
Concept ID:
C0700501
Congenital Abnormality
Nystagmus dating from or present at birth.
Retinal dystrophy
MedGen UID:
208903
Concept ID:
C0854723
Finding
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.
Cerebral visual impairment
MedGen UID:
890568
Concept ID:
C4048268
Pathologic Function
A form of loss of vision caused by damage to the visual cortex rather than a defect in the eye.
Divergence nystagmus
MedGen UID:
892573
Concept ID:
C4073130
Finding
A condition in which both eyes beat outward simultaneously.

Recent clinical studies

Etiology

Yunisova G, Tufekcioglu Z, Dogu O, Bilgic B, Kaleagasi H, Akca Kalem S, Lohmann E, Gurvit HI, Emre M, Hanagasi HA
Neurodegener Dis 2019;19(5-6):218-224. Epub 2020 Apr 29 doi: 10.1159/000506770. PMID: 32349000
Pekeles H, Accogli A, Boudrahem-Addour N, Russell L, Parente F, Srour M
Pediatr Neurol 2019 Mar;92:32-36. Epub 2018 Nov 22 doi: 10.1016/j.pediatrneurol.2018.11.005. PMID: 30581057
Forsythe E, Sparks K, Best S, Borrows S, Hoskins B, Sabir A, Barrett T, Williams D, Mohammed S, Goldsmith D, Milford DV, Bockenhauer D, Foggensteiner L, Beales PL
J Am Soc Nephrol 2017 Mar;28(3):963-970. Epub 2016 Sep 22 doi: 10.1681/ASN.2015091029. PMID: 27659767Free PMC Article
Nowaczyk MJ, Tan M, Hamid JS, Allanson JE
Am J Med Genet A 2012 May;158A(5):1020-8. Epub 2012 Mar 21 doi: 10.1002/ajmg.a.35285. PMID: 22438180
Mäenpää J
Arch Dis Child 1972 Dec;47(256):914-23. doi: 10.1136/adc.47.256.914. PMID: 4119068Free PMC Article

Diagnosis

Nagarajan B, Gowda VK, Yoganathan S, Sharawat IK, Srivastava K, Vora N, Badheka R, Danda S, Kalane U, Kaur A, Madaan P, Mehta S, Negi S, Panda PK, Rajadhyaksha S, Saini AG, Saini L, Shah S, Srinivasan VM, Suthar R, Thomas M, Vyas S, Sankhyan N, Sahu JK
Epilepsia Open 2023 Dec;8(4):1383-1404. Epub 2023 Aug 25 doi: 10.1002/epi4.12811. PMID: 37583270Free PMC Article
Al-Yaarubi S, Al-Abri AS, Al-Kindi H, Al-Abri M, Naz T, Khater D
Sleep Breath 2022 Jun;26(2):815-821. Epub 2021 Aug 9 doi: 10.1007/s11325-021-02463-4. PMID: 34368942
Chang IJ, Byers HM, Ng BG, Merritt JL 2nd, Gilmore R, Shrimal S, Wei W, Zhang Y, Blair AB, Freeze HH, Zhang B, Lam C
J Inherit Metab Dis 2019 Mar;42(2):325-332. Epub 2019 Jan 30 doi: 10.1002/jimd.12021. PMID: 30701557Free PMC Article
Reuter MS, Tawamie H, Buchert R, Hosny Gebril O, Froukh T, Thiel C, Uebe S, Ekici AB, Krumbiegel M, Zweier C, Hoyer J, Eberlein K, Bauer J, Scheller U, Strom TM, Hoffjan S, Abdelraouf ER, Meguid NA, Abboud A, Al Khateeb MA, Fakher M, Hamdan S, Ismael A, Muhammad S, Abdallah E, Sticht H, Wieczorek D, Reis A, Abou Jamra R
JAMA Psychiatry 2017 Mar 1;74(3):293-299. doi: 10.1001/jamapsychiatry.2016.3798. PMID: 28097321
van der Burgt I, Chrzanowska KH, Smeets D, Weemaes C
J Med Genet 1996 Feb;33(2):153-6. doi: 10.1136/jmg.33.2.153. PMID: 8929954Free PMC Article

Therapy

Sevik MO, Aykut A, Şahin Ö
Ophthalmic Genet 2021 Oct;42(5):619-623. Epub 2021 May 11 doi: 10.1080/13816810.2021.1925928. PMID: 33974487
Yunisova G, Tufekcioglu Z, Dogu O, Bilgic B, Kaleagasi H, Akca Kalem S, Lohmann E, Gurvit HI, Emre M, Hanagasi HA
Neurodegener Dis 2019;19(5-6):218-224. Epub 2020 Apr 29 doi: 10.1159/000506770. PMID: 32349000
Matevosyan NR
Arch Gynecol Obstet 2016 Jan;293(1):87-99. Epub 2015 Jun 11 doi: 10.1007/s00404-015-3770-6. PMID: 26063342
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
Rinat C, Zoref-Shani E, Ben-Neriah Z, Bromberg Y, Becker-Cohen R, Feinstein S, Sperling O, Frishberg Y
Mol Genet Metab 2006 Mar;87(3):249-52. Epub 2005 Dec 15 doi: 10.1016/j.ymgme.2005.09.025. PMID: 16343967

Prognosis

Waseem SS, Moawia A, Budde B, Tariq M, Khan A, Ali Z, Khan S, Iqbal M, Malik NA, Haque SU, Altmüller J, Thiele H, Hussain MS, Cirak S, Baig SM, Nürnberg P
Genes (Basel) 2021 Sep 24;12(10) doi: 10.3390/genes12101494. PMID: 34680889Free PMC Article
Bellad A, Girimaji SC, Muthusamy B
Neurol Sci 2021 Dec;42(12):5311-5319. Epub 2021 Apr 21 doi: 10.1007/s10072-021-05262-7. PMID: 33884525
Yunisova G, Tufekcioglu Z, Dogu O, Bilgic B, Kaleagasi H, Akca Kalem S, Lohmann E, Gurvit HI, Emre M, Hanagasi HA
Neurodegener Dis 2019;19(5-6):218-224. Epub 2020 Apr 29 doi: 10.1159/000506770. PMID: 32349000
Schüle R, Schlipf N, Synofzik M, Klebe S, Klimpe S, Hehr U, Winner B, Lindig T, Dotzer A, Riess O, Winkler J, Schöls L, Bauer P
J Neurol Neurosurg Psychiatry 2009 Dec;80(12):1402-4. doi: 10.1136/jnnp.2008.167528. PMID: 19917823
Mäenpää J
Arch Dis Child 1972 Dec;47(256):914-23. doi: 10.1136/adc.47.256.914. PMID: 4119068Free PMC Article

Clinical prediction guides

Nagarajan B, Gowda VK, Yoganathan S, Sharawat IK, Srivastava K, Vora N, Badheka R, Danda S, Kalane U, Kaur A, Madaan P, Mehta S, Negi S, Panda PK, Rajadhyaksha S, Saini AG, Saini L, Shah S, Srinivasan VM, Suthar R, Thomas M, Vyas S, Sankhyan N, Sahu JK
Epilepsia Open 2023 Dec;8(4):1383-1404. Epub 2023 Aug 25 doi: 10.1002/epi4.12811. PMID: 37583270Free PMC Article
Hashmi JA, Fadhli F, Almatrafi A, Afzal S, Ramzan K, Thiele H, Nürnberg P, Basit S
Brain Dev 2020 Sep;42(8):587-593. Epub 2020 May 10 doi: 10.1016/j.braindev.2020.04.010. PMID: 32402540
Nowaczyk MJ, Tan M, Hamid JS, Allanson JE
Am J Med Genet A 2012 May;158A(5):1020-8. Epub 2012 Mar 21 doi: 10.1002/ajmg.a.35285. PMID: 22438180
Schüle R, Schlipf N, Synofzik M, Klebe S, Klimpe S, Hehr U, Winner B, Lindig T, Dotzer A, Riess O, Winkler J, Schöls L, Bauer P
J Neurol Neurosurg Psychiatry 2009 Dec;80(12):1402-4. doi: 10.1136/jnnp.2008.167528. PMID: 19917823
Mäenpää J
Arch Dis Child 1972 Dec;47(256):914-23. doi: 10.1136/adc.47.256.914. PMID: 4119068Free PMC Article

Recent systematic reviews

Agopiantz M, Corbonnois P, Sorlin A, Bonnet C, Klein M, Hubert N, Pascal-Vigneron V, Jonveaux P, Cuny T, Leheup B, Weryha G
J Endocrinol Invest 2014 Jan;37(1):1-7. Epub 2014 Jan 8 doi: 10.1007/s40618-013-0001-5. PMID: 24464444

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