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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).
 
Gene (location): 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.
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.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Vegetative state
MedGen UID:
182977
Concept ID:
C0917808
Pathologic Function
Absence of wakefulness and conscience, but (in contrast to coma) with involuntary opening of the eyes and movements (such as teeth grinding, yawning, or thrashing of the extremities).
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
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.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
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  
  • CROGVMultiple mitochondrial dysfunctions syndrome 4

Recent clinical studies

Etiology

Alfadhel M, Nashabat M, Alrifai MT, Alshaalan H, Al Mutairi F, Al-Shahrani SA, Plecko B, Almass R, Alsagob M, Almutairi FB, Al-Rumayyan A, Al-Twaijri W, Al-Owain M, Taylor RW, Kaya N
Eur J Paediatr Neurol 2018 Jan;22(1):46-55. Epub 2017 Oct 16 doi: 10.1016/j.ejpn.2017.10.003. PMID: 29122497

Diagnosis

Uzunhan TA, Çakar NE, Seyhan S, Aydin K
Brain Dev 2020 Nov;42(10):756-761. Epub 2020 Aug 1 doi: 10.1016/j.braindev.2020.07.009. PMID: 32747156
Ames EG, Neville KL, McNamara NA, Keegan CE, Elsea SH
Neurology 2020 Jul 28;95(4):184-187. Epub 2020 Jul 15 doi: 10.1212/WNL.0000000000009912. PMID: 32669393
Birjiniuk A, Glinton KE, Villafranco N, Boyer S, Laufman J, Mizerik E, Scott D, Elsea SH, Galambos C, Varghese NP, Scaglia F
Am J Med Genet A 2020 Apr;182(4):755-761. Epub 2020 Jan 22 doi: 10.1002/ajmg.a.61491. PMID: 31970900
Alfadhel M, Nashabat M, Alrifai MT, Alshaalan H, Al Mutairi F, Al-Shahrani SA, Plecko B, Almass R, Alsagob M, Almutairi FB, Al-Rumayyan A, Al-Twaijri W, Al-Owain M, Taylor RW, Kaya N
Eur J Paediatr Neurol 2018 Jan;22(1):46-55. Epub 2017 Oct 16 doi: 10.1016/j.ejpn.2017.10.003. PMID: 29122497
Jin D, Yu T, Zhang L, Wang T, Hu J, Wang Y, Yang XA
J Mol Neurosci 2017 Jun;62(2):255-261. Epub 2017 May 3 doi: 10.1007/s12031-017-0927-8. PMID: 28470589

Prognosis

Uzunhan TA, Çakar NE, Seyhan S, Aydin K
Brain Dev 2020 Nov;42(10):756-761. Epub 2020 Aug 1 doi: 10.1016/j.braindev.2020.07.009. PMID: 32747156
Birjiniuk A, Glinton KE, Villafranco N, Boyer S, Laufman J, Mizerik E, Scott D, Elsea SH, Galambos C, Varghese NP, Scaglia F
Am J Med Genet A 2020 Apr;182(4):755-761. Epub 2020 Jan 22 doi: 10.1002/ajmg.a.61491. PMID: 31970900
Eidi M, Garshasbi M
BMC Neurol 2019 Jul 6;19(1):153. doi: 10.1186/s12883-019-1387-2. PMID: 31279336Free PMC Article

Clinical prediction guides

Eidi M, Garshasbi M
BMC Neurol 2019 Jul 6;19(1):153. doi: 10.1186/s12883-019-1387-2. PMID: 31279336Free PMC Article

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