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Multiple mitochondrial dysfunctions syndrome 2(MMDS2)

MedGen UID:
482008
Concept ID:
C3280378
Disease or Syndrome
Synonyms: MMDS2; MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 2 WITH HYPERGLYCINEMIA
SNOMED CT: Multiple mitochondrial dysfunctions syndrome type 2 (1208486005); MMDS2 - multiple mitochondrial dysfunctions syndrome type 2 (1208486005); BOLA3 (bolA family member 3) deficiency (1208486005)
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): BOLA3 (2p13.1)
 
Monarch Initiative: MONDO:0013675
OMIM®: 614299
Orphanet: ORPHA401874

Definition

Multiple mitochondrial dysfunctions syndrome-2 (MMDS2) with hyperglycinemia is a severe autosomal recessive disorder characterized by developmental regression in infancy. Affected children have an encephalopathic disease course with seizures, spasticity, loss of head control, and abnormal movement. Additional more variable features include optic atrophy, cardiomyopathy, and leukodystrophy. Laboratory studies show increased serum glycine and lactate. Most patients die in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including MMDS2, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014). For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711). [from OMIM]

Additional description

From MedlinePlus Genetics
Affected infants typically have severe brain dysfunction (encephalopathy), which can contribute to weak muscle tone (hypotonia), seizures, and delayed development of mental and movement abilities (psychomotor delay). These infants often have difficulty growing and gaining weight at the expected rate (failure to thrive). Most affected babies have a buildup of a chemical called lactic acid in the body (lactic acidosis), which can be life-threatening. They may also have high levels of a molecule called glycine (hyperglycinemia) or elevated levels of sugar (hyperglycemia) in the blood. Some babies with multiple mitochondrial dysfunctions syndrome have high blood pressure in the blood vessels that connect to the lungs (pulmonary hypertension) or weakening of the heart muscle (cardiomyopathy).

Multiple mitochondrial dysfunctions syndrome is characterized by impairment of cellular structures called mitochondria, which are the energy-producing centers of cells. While certain mitochondrial disorders are caused by impairment of a single stage of energy production, individuals with multiple mitochondrial dysfunctions syndrome have reduced function of more than one stage. The signs and symptoms of this severe condition begin early in life, and affected individuals usually do not live past infancy.  https://medlineplus.gov/genetics/condition/multiple-mitochondrial-dysfunctions-syndrome

Clinical features

From HPO
Primary dilated cardiomyopathy
MedGen UID:
2880
Concept ID:
C0007193
Disease or Syndrome
Familial dilated cardiomyopathy is a genetic form of heart disease. It occurs when heart (cardiac) muscle becomes thin and weakened in at least one chamber of the heart, causing the open area of the chamber to become enlarged (dilated). As a result, the heart is unable to pump blood as efficiently as usual. To compensate, the heart attempts to increase the amount of blood being pumped through the heart, leading to further thinning and weakening of the cardiac muscle. Over time, this condition results in heart failure.\n\nIt usually takes many years for symptoms of familial dilated cardiomyopathy to cause health problems. They typically begin in mid-adulthood, but can occur at any time from infancy to late adulthood. Signs and symptoms of familial dilated cardiomyopathy can include an irregular heartbeat (arrhythmia), shortness of breath (dyspnea), extreme tiredness (fatigue), fainting episodes (syncope), and swelling of the legs and feet. In some cases, the first sign of the disorder is sudden cardiac death. The severity of the condition varies among affected individuals, even in members of the same family.
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
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).
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of fatigue, either physical or mental slowness and sluggishness, with difficulties in initiating or performing simple tasks. Distinguished from apathy which implies indifference and a lack of desire or interest in the task. A person with lethargy may have the desire, but not the energy to engage in personal or socially relevant tasks.
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.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
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.
Abnormality of extrapyramidal motor function
MedGen UID:
115941
Concept ID:
C0234133
Sign or Symptom
A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).
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.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Increased CSF glycine concentration
MedGen UID:
1691638
Concept ID:
C5139615
Finding
Abnormally increased levels of glycine in cerebrospinal fluid.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
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.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Tachypnea
MedGen UID:
66669
Concept ID:
C0231835
Finding
Very rapid breathing.
Respiratory distress
MedGen UID:
96907
Concept ID:
C0476273
Sign or Symptom
Respiratory distress is objectively observable as the physical or emotional consequences from the experience of dyspnea. The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea.
Respiratory failure
MedGen UID:
257837
Concept ID:
C1145670
Disease or Syndrome
A severe form of respiratory insufficiency characterized by inadequate gas exchange such that the levels of oxygen or carbon dioxide cannot be maintained within normal limits.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Hyperglycinemia
MedGen UID:
82817
Concept ID:
C0268559
Disease or Syndrome
An elevated concentration of glycine in the blood.
Reduced tissue glycine cleavage enzyme activity
MedGen UID:
1053784
Concept ID:
CN377977
Finding
Concentration or activity of the glycine cleavage enzyme below the lower limit of normal. This enzyme can be measured in multiple tissues including leukocytes and cultured fibroblasts.
Hyperhidrosis
MedGen UID:
5690
Concept ID:
C0020458
Finding
Abnormal excessive perspiration (sweating) despite the lack of appropriate stimuli like hot and humid weather.
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.
Decreased activity of the pyruvate dehydrogenase complex
MedGen UID:
326605
Concept ID:
C1839888
Finding
Decreased activity of mitochondrial complex I
MedGen UID:
393796
Concept ID:
C2677650
Finding
A reduction in the activity of the mitochondrial respiratory chain complex I, which is part of the electron transport chain in mitochondria.
Decreased activity of mitochondrial complex III
MedGen UID:
460434
Concept ID:
C3149083
Finding
A reduction in the activity of the mitochondrial respiratory chain complex III, which is part of the electron transport chain in mitochondria.
Decreased activity of mitochondrial respiratory chain
MedGen UID:
892840
Concept ID:
C4024609
Finding
Decreased activity of the mitochondrial respiratory chain.
Decreased activity of mitochondrial complex II
MedGen UID:
892305
Concept ID:
C4024705
Finding
A reduction in the activity of the mitochondrial respiratory chain complex II, which is part of the electron transport chain in mitochondria.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMultiple mitochondrial dysfunctions syndrome 2
Follow this link to review classifications for Multiple mitochondrial dysfunctions syndrome 2 in Orphanet.

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
Haack TB, Rolinski B, Haberberger B, Zimmermann F, Schum J, Strecker V, Graf E, Athing U, Hoppen T, Wittig I, Sperl W, Freisinger P, Mayr JA, Strom TM, Meitinger T, Prokisch H
J Inherit Metab Dis 2013 Jan;36(1):55-62. Epub 2012 May 5 doi: 10.1007/s10545-012-9489-7. PMID: 22562699

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
Wongkittichote P, Pantano C, Bogush E, Alves CAP, Hong X, He M, Demczko MM, Ganetzky RD, Goldstein A
Mol Genet Metab 2023 Sep-Oct;140(1-2):107710. Epub 2023 Oct 20 doi: 10.1016/j.ymgme.2023.107710. PMID: 37903659
Nikam RM, Gripp KW, Choudhary AK, Kandula V
Am J Med Genet A 2018 Dec;176(12):2787-2790. Epub 2018 Oct 10 doi: 10.1002/ajmg.a.40490. PMID: 30302924
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
Haack TB, Rolinski B, Haberberger B, Zimmermann F, Schum J, Strecker V, Graf E, Athing U, Hoppen T, Wittig I, Sperl W, Freisinger P, Mayr JA, Strom TM, Meitinger T, Prokisch H
J Inherit Metab Dis 2013 Jan;36(1):55-62. Epub 2012 May 5 doi: 10.1007/s10545-012-9489-7. PMID: 22562699

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

Wongkittichote P, Pantano C, Bogush E, Alves CAP, Hong X, He M, Demczko MM, Ganetzky RD, Goldstein A
Mol Genet Metab 2023 Sep-Oct;140(1-2):107710. Epub 2023 Oct 20 doi: 10.1016/j.ymgme.2023.107710. PMID: 37903659
Bargagna B, Banci L, Camponeschi F
Int J Mol Sci 2023 Jul 21;24(14) doi: 10.3390/ijms241411734. PMID: 37511493Free PMC Article
Saudino G, Suraci D, Nasta V, Ciofi-Baffoni S, Banci L
Int J Mol Sci 2021 May 3;22(9) doi: 10.3390/ijms22094848. PMID: 34063696Free PMC Article
Jain A, Singh A, Maio N, Rouault TA
Hum Mol Genet 2020 Nov 25;29(19):3165-3182. doi: 10.1093/hmg/ddaa172. PMID: 32776106Free PMC Article

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