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Glycosylphosphatidylinositol biosynthesis defect 15(GPIBD15)

MedGen UID:
1615160
Concept ID:
C4540520
Disease or Syndrome
Synonym: DEVELOPMENTAL DELAY, EPILEPSY, CEREBELLAR ATROPHY, AND OSTEOPENIA
SNOMED CT: Neurodevelopmental delay, seizures, ophthalmic anomalies, osteopenia, cerebellar atrophy syndrome (1217381009); GPAA1-related biosynthesis defect (1217381009); Glycosylphosphatidylinositol anchor attachment 1-related biosynthesis defect (1217381009)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
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).
 
Gene (location): GPAA1 (8q24.3)
 
Monarch Initiative: MONDO:0060627
OMIM®: 617810
Orphanet: ORPHA529665

Definition

GPIBD15 is an autosomal recessive disorder characterized by delayed psychomotor development, variable intellectual disability, hypotonia, early-onset seizures in most patients, and cerebellar atrophy, resulting in cerebellar signs including gait ataxia and dysarthria. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis (summary by Nguyen et al., 2017). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293). [from OMIM]

Clinical features

From HPO
Apraxia
MedGen UID:
8166
Concept ID:
C0003635
Mental or Behavioral Dysfunction
A defect in the understanding of complex motor commands and in the execution of certain learned movements, i.e., deficits in the cognitive components of learned movements.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
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.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
EEG abnormality
MedGen UID:
56235
Concept ID:
C0151611
Finding
Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Dysmetria
MedGen UID:
68583
Concept ID:
C0234162
Finding
A type of ataxia characterized by the inability to carry out movements with the correct range and motion across the plane of more than one joint related to incorrect estimation of the distances required for targeted movements.
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.
Atonic seizure
MedGen UID:
78735
Concept ID:
C0270846
Disease or Syndrome
Atonic seizure is a type of motor seizure characterized by a sudden loss or diminution of muscle tone without apparent preceding myoclonic or tonic event lasting about 1 to 2 seconds, involving head, trunk, jaw, or limb musculature.
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.
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Incapability to ambulate.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
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.
Gait ataxia
MedGen UID:
155642
Concept ID:
C0751837
Sign or Symptom
A type of ataxia characterized by the impairment of the ability to coordinate the movements required for normal walking. Gait ataxia is characteirzed by a wide-based staggering gait with a tendency to fall.
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.
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.
Myoclonic seizure
MedGen UID:
1385980
Concept ID:
C4317123
Sign or Symptom
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.
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.
Osteopenia
MedGen UID:
18222
Concept ID:
C0029453
Disease or Syndrome
Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.
Prominent forehead
MedGen UID:
373291
Concept ID:
C1837260
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Narrow forehead
MedGen UID:
326956
Concept ID:
C1839758
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations below the mean (objective); or apparently narrow intertemporal region (subjective).
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Myopia
MedGen UID:
44558
Concept ID:
C0027092
Disease or Syndrome
Nearsightedness, also known as myopia, is an eye condition that causes blurry distance vision. People who are nearsighted have more trouble seeing things that are far away (such as when driving) than things that are close up (such as when reading or using a computer). If it is not treated with corrective lenses or surgery, nearsightedness can lead to squinting, eyestrain, headaches, and significant visual impairment.\n\nNearsightedness usually begins in childhood or adolescence. It tends to worsen with age until adulthood, when it may stop getting worse (stabilize). In some people, nearsightedness improves in later adulthood.\n\nFor normal vision, light passes through the clear cornea at the front of the eye and is focused by the lens onto the surface of the retina, which is the lining of the back of the eye that contains light-sensing cells. People who are nearsighted typically have eyeballs that are too long from front to back. As a result, light entering the eye is focused too far forward, in front of the retina instead of on its surface. It is this change that causes distant objects to appear blurry. The longer the eyeball is, the farther forward light rays will be focused and the more severely nearsighted a person will be.\n\nNearsightedness is measured by how powerful a lens must be to correct it. The standard unit of lens power is called a diopter. Negative (minus) powered lenses are used to correct nearsightedness. The more severe a person's nearsightedness, the larger the number of diopters required for correction. In an individual with nearsightedness, one eye may be more nearsighted than the other.\n\nEye doctors often refer to nearsightedness less than -5 or -6 diopters as "common myopia." Nearsightedness of -6 diopters or more is commonly called "high myopia." This distinction is important because high myopia increases a person's risk of developing other eye problems that can lead to permanent vision loss or blindness. These problems include tearing and detachment of the retina, clouding of the lens (cataract), and an eye disease called glaucoma that is usually related to increased pressure within the eye. The risk of these other eye problems increases with the severity of the nearsightedness. The term "pathological myopia" is used to describe cases in which high myopia leads to tissue damage within the eye.
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.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
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.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVGlycosylphosphatidylinositol biosynthesis defect 15

Recent clinical studies

Etiology

Lam C, Scaglia F, Berry GT, Larson A, Sarafoglou K, Andersson HC, Sklirou E, Tan QKG, Starosta RT, Sadek M, Wolfe L, Horikoshi S, Ali M, Barone R, Campbell T, Chang IJ, Coles K, Cook E, Eklund EA, Engelhardt NM, Freeman M, Friedman J, Fu DYT, Botzo G, Rawls B, Hernandez C, Johnsen C, Keller K, Kramer S, Kuschel B, Leshinski A, Martinez-Duncker I, Mazza GL, Mercimek-Andrews S, Miller BS, Muthusamy K, Neira J, Patterson MC, Pogorelc N, Powers LN, Ramey E, Reinhart M, Squire A, Thies J, Vockley J, Vreugdenhil H, Witters P, Youbi M, Zeighami A, Zemet R, Edmondson AC, Morava E
Mol Genet Metab 2024 Aug;142(4):108509. Epub 2024 Jun 6 doi: 10.1016/j.ymgme.2024.108509. PMID: 38959600Free PMC Article
Kang M, Wu M, Crane JL
Bone 2023 Jul;172:116778. Epub 2023 Apr 21 doi: 10.1016/j.bone.2023.116778. PMID: 37088336Free PMC Article
Bayat A, Kløvgaard M, Johannesen KM, Barakat TS, Kievit A, Montomoli M, Parrini E, Pietrafusa N, Schelhaas J, van Slegtenhorst M, Miya K, Guerrini R, Tranebjærg L, Tümer Z, Rubboli G, Møller RS
Epilepsy Res 2021 Feb;170:106530. Epub 2020 Dec 9 doi: 10.1016/j.eplepsyres.2020.106530. PMID: 33508693
Carmody LC, Blau H, Danis D, Zhang XA, Gourdine JP, Vasilevsky N, Krawitz P, Thompson MD, Robinson PN
Orphanet J Rare Dis 2020 Feb 4;15(1):40. doi: 10.1186/s13023-020-1313-0. PMID: 32019583Free PMC Article

Diagnosis

Lam C, Scaglia F, Berry GT, Larson A, Sarafoglou K, Andersson HC, Sklirou E, Tan QKG, Starosta RT, Sadek M, Wolfe L, Horikoshi S, Ali M, Barone R, Campbell T, Chang IJ, Coles K, Cook E, Eklund EA, Engelhardt NM, Freeman M, Friedman J, Fu DYT, Botzo G, Rawls B, Hernandez C, Johnsen C, Keller K, Kramer S, Kuschel B, Leshinski A, Martinez-Duncker I, Mazza GL, Mercimek-Andrews S, Miller BS, Muthusamy K, Neira J, Patterson MC, Pogorelc N, Powers LN, Ramey E, Reinhart M, Squire A, Thies J, Vockley J, Vreugdenhil H, Witters P, Youbi M, Zeighami A, Zemet R, Edmondson AC, Morava E
Mol Genet Metab 2024 Aug;142(4):108509. Epub 2024 Jun 6 doi: 10.1016/j.ymgme.2024.108509. PMID: 38959600Free PMC Article
Fontana P, Budillon A, Simeone D, Del Vecchio Blanco F, Caiazza M, D'Amico A, Lonardo F, Nigro V, Limongelli G, Scarano G
Genes (Basel) 2023 Jul 14;14(7) doi: 10.3390/genes14071444. PMID: 37510348Free PMC Article
Kim P, Scott MR, Meador-Woodruff JH
Transl Psychiatry 2019 Jan 16;9(1):6. doi: 10.1038/s41398-018-0359-4. PMID: 30664618Free PMC Article
Yang J, Wang Q, Zhuo Q, Tian H, Li W, Luo F, Zhang J, Bi D, Peng J, Zhou D, Xin H
Mol Genet Genomic Med 2018 Sep;6(5):739-748. Epub 2018 Jul 4 doi: 10.1002/mgg3.428. PMID: 29974678Free PMC Article
Chabane S, Sarfati J, Ibrahim-Granet O, Du C, Schmidt C, Mouyna I, Prevost MC, Calderone R, Latgé JP
Appl Environ Microbiol 2006 May;72(5):3259-67. doi: 10.1128/AEM.72.5.3259-3267.2006. PMID: 16672465Free PMC Article

Therapy

Lam C, Scaglia F, Berry GT, Larson A, Sarafoglou K, Andersson HC, Sklirou E, Tan QKG, Starosta RT, Sadek M, Wolfe L, Horikoshi S, Ali M, Barone R, Campbell T, Chang IJ, Coles K, Cook E, Eklund EA, Engelhardt NM, Freeman M, Friedman J, Fu DYT, Botzo G, Rawls B, Hernandez C, Johnsen C, Keller K, Kramer S, Kuschel B, Leshinski A, Martinez-Duncker I, Mazza GL, Mercimek-Andrews S, Miller BS, Muthusamy K, Neira J, Patterson MC, Pogorelc N, Powers LN, Ramey E, Reinhart M, Squire A, Thies J, Vockley J, Vreugdenhil H, Witters P, Youbi M, Zeighami A, Zemet R, Edmondson AC, Morava E
Mol Genet Metab 2024 Aug;142(4):108509. Epub 2024 Jun 6 doi: 10.1016/j.ymgme.2024.108509. PMID: 38959600Free PMC Article
Gabaldon-Albero A, Cordon L, Sempere A, Pedrola L, Martin-Grau C, Oltra S, Monfort S, Caro-Llopis A, Dominguez-Martinez M, Hernandez-Muela S, Rosello M, Orellana C, Martinez F
Genes (Basel) 2024 Jun 18;15(6) doi: 10.3390/genes15060802. PMID: 38927738Free PMC Article
Kang M, Wu M, Crane JL
Bone 2023 Jul;172:116778. Epub 2023 Apr 21 doi: 10.1016/j.bone.2023.116778. PMID: 37088336Free PMC Article
Yamada N, Miyata T, Maeda K, Kitani T, Takeda J, Kinoshita T
Blood 1995 Feb 15;85(4):885-92. PMID: 7531514

Prognosis

Lam C, Scaglia F, Berry GT, Larson A, Sarafoglou K, Andersson HC, Sklirou E, Tan QKG, Starosta RT, Sadek M, Wolfe L, Horikoshi S, Ali M, Barone R, Campbell T, Chang IJ, Coles K, Cook E, Eklund EA, Engelhardt NM, Freeman M, Friedman J, Fu DYT, Botzo G, Rawls B, Hernandez C, Johnsen C, Keller K, Kramer S, Kuschel B, Leshinski A, Martinez-Duncker I, Mazza GL, Mercimek-Andrews S, Miller BS, Muthusamy K, Neira J, Patterson MC, Pogorelc N, Powers LN, Ramey E, Reinhart M, Squire A, Thies J, Vockley J, Vreugdenhil H, Witters P, Youbi M, Zeighami A, Zemet R, Edmondson AC, Morava E
Mol Genet Metab 2024 Aug;142(4):108509. Epub 2024 Jun 6 doi: 10.1016/j.ymgme.2024.108509. PMID: 38959600Free PMC Article
Bayat A, Kløvgaard M, Johannesen KM, Barakat TS, Kievit A, Montomoli M, Parrini E, Pietrafusa N, Schelhaas J, van Slegtenhorst M, Miya K, Guerrini R, Tranebjærg L, Tümer Z, Rubboli G, Møller RS
Epilepsy Res 2021 Feb;170:106530. Epub 2020 Dec 9 doi: 10.1016/j.eplepsyres.2020.106530. PMID: 33508693
Yang J, Wang Q, Zhuo Q, Tian H, Li W, Luo F, Zhang J, Bi D, Peng J, Zhou D, Xin H
Mol Genet Genomic Med 2018 Sep;6(5):739-748. Epub 2018 Jul 4 doi: 10.1002/mgg3.428. PMID: 29974678Free PMC Article
Rosse WF
Medicine (Baltimore) 1997 Mar;76(2):63-93. doi: 10.1097/00005792-199703000-00001. PMID: 9100736
Saporito-Irwin SM, Birse CE, Sypherd PS, Fonzi WA
Mol Cell Biol 1995 Feb;15(2):601-13. doi: 10.1128/MCB.15.2.601. PMID: 7823929Free PMC Article

Clinical prediction guides

Lam C, Scaglia F, Berry GT, Larson A, Sarafoglou K, Andersson HC, Sklirou E, Tan QKG, Starosta RT, Sadek M, Wolfe L, Horikoshi S, Ali M, Barone R, Campbell T, Chang IJ, Coles K, Cook E, Eklund EA, Engelhardt NM, Freeman M, Friedman J, Fu DYT, Botzo G, Rawls B, Hernandez C, Johnsen C, Keller K, Kramer S, Kuschel B, Leshinski A, Martinez-Duncker I, Mazza GL, Mercimek-Andrews S, Miller BS, Muthusamy K, Neira J, Patterson MC, Pogorelc N, Powers LN, Ramey E, Reinhart M, Squire A, Thies J, Vockley J, Vreugdenhil H, Witters P, Youbi M, Zeighami A, Zemet R, Edmondson AC, Morava E
Mol Genet Metab 2024 Aug;142(4):108509. Epub 2024 Jun 6 doi: 10.1016/j.ymgme.2024.108509. PMID: 38959600Free PMC Article
Bayat A, Kløvgaard M, Johannesen KM, Barakat TS, Kievit A, Montomoli M, Parrini E, Pietrafusa N, Schelhaas J, van Slegtenhorst M, Miya K, Guerrini R, Tranebjærg L, Tümer Z, Rubboli G, Møller RS
Epilepsy Res 2021 Feb;170:106530. Epub 2020 Dec 9 doi: 10.1016/j.eplepsyres.2020.106530. PMID: 33508693
Kim P, Scott MR, Meador-Woodruff JH
Transl Psychiatry 2019 Jan 16;9(1):6. doi: 10.1038/s41398-018-0359-4. PMID: 30664618Free PMC Article
Yang J, Wang Q, Zhuo Q, Tian H, Li W, Luo F, Zhang J, Bi D, Peng J, Zhou D, Xin H
Mol Genet Genomic Med 2018 Sep;6(5):739-748. Epub 2018 Jul 4 doi: 10.1002/mgg3.428. PMID: 29974678Free PMC Article
Saporito-Irwin SM, Birse CE, Sypherd PS, Fonzi WA
Mol Cell Biol 1995 Feb;15(2):601-13. doi: 10.1128/MCB.15.2.601. PMID: 7823929Free PMC Article

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