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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3(MDDGA3)

MedGen UID:
462869
Concept ID:
C3151519
Disease or Syndrome
Synonyms: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 3; WALKER-WARBURG SYNDROME OR MUSCLE-EYE-BRAIN DISEASE, POMGNT1-RELATED
Modes of inheritance:
Heterogeneous
MedGen UID:
67020
Concept ID:
C0242960
Organism Attribute
Source: HPO
The presence of apparently similar characters for which the genetic evidence indicates that different genes or different genetic mechanisms are involved in different pedigrees. In clinical settings genetic heterogeneity refers to the presence of a variety of genetic defects which cause the same disease, often due to mutations at different loci on the same gene, a finding common to many human diseases including ALZHEIMER DISEASE; CYSTIC FIBROSIS; LIPOPROTEIN LIPASE DEFICIENCY, FAMILIAL; and POLYCYSTIC KIDNEY DISEASES. (Rieger, et al., Glossary of Genetics: Classical and Molecular, 5th ed; Segen, Dictionary of Modern Medicine, 1992)
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM
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): POMGNT1 (1p34.1)
 
Monarch Initiative: MONDO:0009667
OMIM®: 253280

Definition

An autosomal recessive muscular dystrophy caused by mutations in the POMGNT1 gene. It is associated with characteristic brain and eye malformations, profound mental retardation, and death usually in the first years of life. [from NCI]

Clinical features

From HPO
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
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.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Sign or Symptom
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Seizures
MedGen UID:
20693
Concept ID:
C0036572
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.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
IQ 20-34.
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.
Polymicrogyria
MedGen UID:
78605
Concept ID:
C0266464
Congenital Abnormality
Polymicrogyria is a congenital malformation of the cerebral cortex characterized by abnormal cortical layering (lamination) and an excessive number of small gyri (folds).
Congenital cerebellar hypoplasia
MedGen UID:
120578
Concept ID:
C0266470
Congenital Abnormality
Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay is an autosomal recessive neurodevelopmental disorder characterized by infantile onset of hypotonia and developmental delay with subsequent impaired intellectual development and severe speech delay. In childhood, affected individuals show delayed walking and develop epilepsy that is usually controlled by medication. Brain imaging shows cerebellar hypoplasia/atrophy (summary by Wang et al., 2019).
Macrogyria
MedGen UID:
120579
Concept ID:
C0266483
Congenital Abnormality
Pachygyria is a malformation of cortical development with abnormally wide gyri with sulci 1,5-3 cm apart and abnormally thick cortex measuring more than 5 mm (radiological definition). See also neuropathological definitions for 2-, 3-, and 4-layered lissencephaly.
Type II lissencephaly
MedGen UID:
96562
Concept ID:
C0431376
Congenital Abnormality
A form of lissencephaly characterized by an uneven cortical surface with a so called 'cobblestone' appearace. There are no distinguishable cortical layers.
Severe global developmental delay
MedGen UID:
332436
Concept ID:
C1837397
Finding
A severe delay in the achievement of motor or mental milestones in the domains of development of a child.
Hypoplasia of the brainstem
MedGen UID:
334226
Concept ID:
C1842688
Finding
Underdevelopment of the brainstem.
Cerebellar cyst
MedGen UID:
339835
Concept ID:
C1847762
Finding
Aplasia/Hypoplasia of the corpus callosum
MedGen UID:
354608
Concept ID:
C1861866
Finding
Absence or underdevelopment of the corpus callosum.
Intellectual disability, profound
MedGen UID:
892508
Concept ID:
C3161330
Mental or Behavioral Dysfunction
Cerebellar dysplasia
MedGen UID:
479952
Concept ID:
C3278322
Finding
Cerebellar dysplasia (abnormal growth or development) is defined by abnormal cerebellar foliation, white matter arborization, and gray-white matter junction. Cerebellar dysplasia is a neuroimaging finding that describes abnormalities of both the cerebellar cortex and white matter and is associated with variable neurodevelopmental outcome. Dysplasia may globally involve the cerebellum or affect only one cerebellar hemisphere. In addition, cerebellar dysplasia may be associated with cortical/subcortical cysts.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
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.
Muscular dystrophy
MedGen UID:
44527
Concept ID:
C0026850
Disease or Syndrome
A group of inherited progressive muscle disorders characterized by muscle weakness and eventual death of the muscle tissues. Examples include Duchenne muscular dystrophy, Becker's muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, and limb-girdle muscular dystrophy.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
A reduction in the strength of one or more muscles.
Generalized muscle weakness
MedGen UID:
155433
Concept ID:
C0746674
Sign or Symptom
Generalized weakness or decreased strength of the muscles, affecting both distal and proximal musculature.
Severe muscular hypotonia
MedGen UID:
326544
Concept ID:
C1839630
Finding
A severe degree of muscular hypotonia characterized by markedly reduced muscle tone.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Anatomical Abnormality
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase, CPK; EC 2.7.3.2) in the blood. CPK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Everted lower lip vermilion
MedGen UID:
344003
Concept ID:
C1853246
Finding
An abnormal configuration of the lower lip such that it is turned outward i.e., everted, with the Inner aspect of the lower lip vermilion (normally opposing the teeth) being visible in a frontal view.
Short nasal bridge
MedGen UID:
340281
Concept ID:
C1854689
Finding
Decreased superior-inferior length of the nasal bridge, which is the saddle-shaped area that includes the nasal root and the lateral aspects of the nose.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Anatomical Abnormality
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Midface retrusion
MedGen UID:
388629
Concept ID:
C2673410
Finding
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Pallor
MedGen UID:
10547
Concept ID:
C0030232
Finding
Abnormally pale skin.
Congenital ocular coloboma
MedGen UID:
1046
Concept ID:
C0009363
Congenital Abnormality
Coloboma is an ocular birth defect resulting from abnormal development of the eye during embryogenesis. It is defined as a congenital defect in any ocular tissue, typically presenting as absent tissue or a gap, at a site consistent with aberrant closure of the optic fissure. Failure of fusion can lead to coloboma of one or multiple regions of the inferior portion of the eye affecting any part of the globe traversed by the fissure, from the iris to the optic nerve, including the ciliary body, retina, and choroid. Coloboma is also frequently associated with small (microphthalmic) or absent (anophthalmic) eyes as part of an interrelated spectrum of developmental eye anomalies, and can affect either one or both eyes (summary by Kelberman et al., 2014). Genetic Heterogeneity of Ocular Coloboma A recessive form of ocular coloboma (216820) is caused by mutation in the SALL2 gene (602219) on chromosome 14q11.
Glaucoma
MedGen UID:
42224
Concept ID:
C0017601
Disease or Syndrome
Glaucoma refers loss of retinal ganglion cells in a characteristic pattern of optic neuropathy usually associated with increased intraocular pressure.
Microphthalmia
MedGen UID:
10033
Concept ID:
C0026010
Congenital Abnormality
Microphthalmia is an eye abnormality that arises before birth. In this condition, one or both eyeballs are abnormally small. In some affected individuals, the eyeball may appear to be completely missing; however, even in these cases some remaining eye tissue is generally present. Such severe microphthalmia should be distinguished from another condition called anophthalmia, in which no eyeball forms at all. However, the terms anophthalmia and severe microphthalmia are often used interchangeably. Microphthalmia may or may not result in significant vision loss.\n\nPeople with microphthalmia may also have a condition called coloboma. Colobomas are missing pieces of tissue in structures that form the eye. They may appear as notches or gaps in the colored part of the eye called the iris; the retina, which is the specialized light-sensitive tissue that lines the back of the eye; the blood vessel layer under the retina called the choroid; or in the optic nerves, which carry information from the eyes to the brain. Colobomas may be present in one or both eyes and, depending on their size and location, can affect a person's vision.\n\nPeople with microphthalmia may also have other eye abnormalities, including clouding of the lens of the eye (cataract) and a narrowed opening of the eye (narrowed palpebral fissure). Additionally, affected individuals may have an abnormality called microcornea, in which the clear front covering of the eye (cornea) is small and abnormally curved.\n\nBetween one-third and one-half of affected individuals have microphthalmia as part of a syndrome that affects other organs and tissues in the body. These forms of the condition are described as syndromic. When microphthalmia occurs by itself, it is described as nonsyndromic or isolated.
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
A disorder characterized by loss of optic nerve fibers. It may be inherited or acquired. Acquired causes include ischemia, optic nerve neuropathy, glaucoma, trauma, radiation, brain tumors, and multiple sclerosis. It leads to vision disturbances.
Retinal degeneration
MedGen UID:
48432
Concept ID:
C0035304
Finding
Degeneration of the retina.
Retinal dysplasia
MedGen UID:
48433
Concept ID:
C0035313
Congenital Abnormality
Congenital, often bilateral, retinal abnormality characterized by the arrangement of outer nuclear retinal cells in a palisading or radiating pattern surrounding a central ocular space. This disorder is sometimes hereditary.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Acquired Abnormality
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Megalocornea
MedGen UID:
138008
Concept ID:
C0344530
Congenital Abnormality
Megalocornea is an inherited eye disorder in which the corneal diameter is bilaterally enlarged (greater than 13 mm) without an increase in intraocular pressure. It may also be referred to as 'anterior megalophthalmos,' since the entire anterior segment is larger than normal. Features of megalocornea in addition to a deep anterior chamber include astigmatic refractive errors, atrophy of the iris stroma, miosis secondary to decreased function of the dilator muscle, iridodonesis, and tremulousness, subluxation, or dislocation of the lens. Whereas most affected individuals exhibit normal ocular function, complications include cataract development and glaucoma following lenticular dislocation or subluxation. X-linked recessive inheritance is the most common pattern, accounting for the male preponderance of the disorder (summary by Skuta et al., 1983). Megalocornea sometimes occurs as part of the Marfan syndrome (154700). Genetic Heterogeneity of Megalocornea Autosomal recessive megalocornea has been reported (249300).
Opacification of the corneal stroma
MedGen UID:
602191
Concept ID:
C0423250
Finding
Reduced transparency of the stroma of cornea.
Retinal atrophy
MedGen UID:
101075
Concept ID:
C0521694
Disease or Syndrome
Well-demarcated area(s) of partial or complete depigmentation in the fundus, reflecting atrophy of the retinal pigment epithelium with associated retinal photoreceptor loss.
Decreased light- and dark-adapted electroretinogram amplitude
MedGen UID:
326793
Concept ID:
C1839025
Finding
Descreased amplitude of eletrical response upon electroretinography.
Hypoplasia of the retina
MedGen UID:
344343
Concept ID:
C1854685
Congenital Abnormality
Uncontrolled eye movements
MedGen UID:
340279
Concept ID:
C1854686
Finding
Undetectable electroretinogram
MedGen UID:
383742
Concept ID:
C1855685
Finding
Lack of any response to stimulation upon electroretinography.
Enlarged flash visual evoked potentials
MedGen UID:
867200
Concept ID:
C4021558
Finding
Buphthalmos
MedGen UID:
1641795
Concept ID:
C4551507
Congenital Abnormality
Diffusely large eye (with megalocornea) associated with glaucoma.

Term Hierarchy

Recent clinical studies

Etiology

Borisovna KO, Yurievna KA, Yurievich TK, Igorevna KO, Olegovich KD, Igorevna DA, Timofeevna BT, Vyacheslavovna ZN, Ivanovna SE, Alekseevich SP, Vladimirovich IV
BMC Pediatr 2019 Apr 8;19(1):98. doi: 10.1186/s12887-019-1470-2. PMID: 30961548Free PMC Article

Diagnosis

Arvio M, Määttänen L, Haanpää M, Lähdetie J
Am J Med Genet A 2019 Dec;179(12):2481-2485. Epub 2019 Oct 3 doi: 10.1002/ajmg.a.61369. PMID: 31580529
Borisovna KO, Yurievna KA, Yurievich TK, Igorevna KO, Olegovich KD, Igorevna DA, Timofeevna BT, Vyacheslavovna ZN, Ivanovna SE, Alekseevich SP, Vladimirovich IV
BMC Pediatr 2019 Apr 8;19(1):98. doi: 10.1186/s12887-019-1470-2. PMID: 30961548Free PMC Article

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