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Multiple mitochondrial dysfunctions syndrome 6(MMDS6)

MedGen UID:
1643082
Concept ID:
C4693741
Disease or Syndrome
Synonyms: MMDS6; MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 6
SNOMED CT: PMPCB (peptidase mitochondrial processing subunit beta) deficiency (1279891002); PMPCB deficiency (1279891002); Multiple mitochondrial dysfunctions syndrome type 6 (1279891002)
 
Gene (location): PMPCB (7q22.1)
 
Monarch Initiative: MONDO:0054785
OMIM®: 617954
Orphanet: ORPHA569290

Definition

Multiple mitochondrial dysfunctions syndrome-6 is an autosomal recessive severe neurodegenerative disorder with onset in early childhood. Affected individuals may have initial normal development, but show neurologic regression in the first year of life. They have hypotonia, inability to walk, poor speech, intellectual disability, and motor abnormalities, such as ataxia, dystonia, and spasticity. Some patients may die in childhood. Laboratory evidence indicates that the disorder results from mitochondrial dysfunction (summary by Vogtle et al., 2018). For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711). [from OMIM]

Clinical features

From HPO
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.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
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.
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.
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.
Leukoencephalopathy
MedGen UID:
78722
Concept ID:
C0270612
Disease or Syndrome
This term describes abnormality of the white matter of the cerebrum resulting from damage to the myelin sheaths of nerve cells.
Epileptic encephalopathy
MedGen UID:
452596
Concept ID:
C0543888
Disease or Syndrome
A condition in which epileptiform abnormalities are believed to contribute to the progressive disturbance in cerebral function. Epileptic encephalaopathy is characterized by (1) electrographic EEG paroxysmal activity that is often aggressive, (2) seizures that are usually multiform and intractable, (3) cognitive, behavioral and neurological deficits that may be relentless, and (4) sometimes early death.
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.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
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.
Atrophy/Degeneration affecting the brainstem
MedGen UID:
870454
Concept ID:
C4024900
Disease or Syndrome
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.
Secondary microcephaly
MedGen UID:
608952
Concept ID:
C0431352
Finding
Head circumference which falls below 2 standard deviations below the mean for age and gender because of insufficient head growth after birth.
Poor head control
MedGen UID:
322809
Concept ID:
C1836038
Finding
Difficulty to maintain correct position of the head while standing or sitting. Infant head lag is observed when the head seems to flop around or lags posteriorly behind the trunk. Several articles have maintained that head lag should be absent by age 3 to 4 months.
Increased circulating lactate concentration
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
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 loss
MedGen UID:
784038
Concept ID:
C3665386
Finding
Loss of visual acuity (implying that vision was better at a certain time point in life). Otherwise the term reduced visual acuity should be used (or a subclass of that).

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMultiple mitochondrial dysfunctions syndrome 6

Recent clinical studies

Etiology

Debray FG, Stümpfig C, Vanlander AV, Dideberg V, Josse C, Caberg JH, Boemer F, Bours V, Stevens R, Seneca S, Smet J, Lill R, van Coster R
J Inherit Metab Dis 2015 Nov;38(6):1147-53. Epub 2015 May 14 doi: 10.1007/s10545-015-9857-1. PMID: 25971455

Diagnosis

Xu H, Ma K, Gao Y, Song Q, Chen C, Xu X, Peng J, Sun Y
Mol Genet Genomic Med 2024 Jun;12(6):e2485. doi: 10.1002/mgg3.2485. PMID: 38923322Free PMC Article
Debray FG, Stümpfig C, Vanlander AV, Dideberg V, Josse C, Caberg JH, Boemer F, Bours V, Stevens R, Seneca S, Smet J, Lill R, van Coster R
J Inherit Metab Dis 2015 Nov;38(6):1147-53. Epub 2015 May 14 doi: 10.1007/s10545-015-9857-1. PMID: 25971455

Prognosis

Debray FG, Stümpfig C, Vanlander AV, Dideberg V, Josse C, Caberg JH, Boemer F, Bours V, Stevens R, Seneca S, Smet J, Lill R, van Coster R
J Inherit Metab Dis 2015 Nov;38(6):1147-53. Epub 2015 May 14 doi: 10.1007/s10545-015-9857-1. PMID: 25971455

Clinical prediction guides

Bargagna B, Banci L, Camponeschi F
Int J Mol Sci 2023 Jul 21;24(14) doi: 10.3390/ijms241411734. PMID: 37511493Free PMC Article

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