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Multiple mitochondrial dysfunctions syndrome 4(MMDS4)

MedGen UID:: 899010
•Concept ID:: C4225348
•: Disease or Syndrome

Synonym:	MMDS4
SNOMED CT:	Multiple mitochondrial dysfunctions syndrome type 4 (1208621008); MMDS4 - multiple mitochondrial dysfunctions syndrome type 4 (1208621008)
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). Autosomal recessive inheritance (Orphanet)

Gene (location): Gene(s) directly associated with this condition or phenotype.	ISCA2 (14q24.3)

Monarch Initiative:	MONDO:0014611
OMIM®:	616370
Orphanet:	ORPHA457406

Disease characteristics

Excerpted from the GeneReview: ISCA2-Related Mitochondrial Disorder

Infants with ISCA2-related mitochondrial disorder (IRMD) typically attain normal development in the first months of life. At age three to seven months, affected individuals usually present with a triad of neurodevelopmental regression, nystagmus with optic atrophy, and diffuse white matter disease. As the disease progresses, global psychomotor regression continues at a variable pace and seizures may develop. Affected children become vegetative within one to two years. During their vegetative state, which may persist for years, affected individuals are prone to recurrent chest infections that may require ventilator support. Most affected individuals die during early childhood. [from GeneReviews]

Authors:
Zuhair N Al-Hassnan | Namik Kaya view full author information

Additional description

From OMIM
MMDS4 is an autosomal recessive neurodegenerative disorder that usually results in death in early childhood. Affected individuals have normal development for the first months of life, but thereafter show progressive loss of motor and social skills with hypotonia, spasticity, and nystagmus. Patients regress to a vegetative state with lack of eye contact and speech, and poor feeding. Most patients have optic atrophy, and some may develop seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased CSF glycine and decreased activity of mitochondrial complex II; there may be additional biochemical evidence of mitochondrial dysfunction (summary by Alaimo et al., 2018). For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711). http://www.omim.org/entry/616370

Clinical features

From HPO

Leukodystrophy

MedGen UID:: 6070
•Concept ID:: C0023520
•: Disease or Syndrome

Leukodystrophy refers to deterioration of white matter of the brain resulting from degeneration of myelin sheaths in the CNS. Their basic defect is directly related to the synthesis and maintenance of myelin membranes. Symmetric white matter involvement at MRI is a typical finding in patients with leukodystrophies.

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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.

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Hyperreflexia

MedGen UID:: 57738
•Concept ID:: C0151889
•: Finding

Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.

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Vegetative state

MedGen UID:: 182977
•Concept ID:: C0917808
•: Pathologic Function

The absence of wakefulness and consciousness, but in contrast to a coma, there is involuntary opening of the eyes and movements such as teeth grinding, yawning, or thrashing of the extremities.

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Developmental regression

MedGen UID:: 324613
•Concept ID:: C1836830
•: Disease or Syndrome

Loss of developmental skills, as manifested by loss of developmental milestones.

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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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Abnormal periventricular white matter morphology

MedGen UID:: 435926
•Concept ID:: C2673431
•: Finding

A structural abnormality of the myelinated axons (white matter) located near the cerebral ventricles.

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Profound global developmental delay

MedGen UID:: 766364
•Concept ID:: C3553450
•: Disease or Syndrome

A profound delay in the achievement of motor or mental milestones in the domains of development of a child.

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Generalized hypotonia

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

Generalized muscular hypotonia (abnormally low muscle tone).

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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.

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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.

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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.

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Decreased activity of mitochondrial complex I