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HSD10 mitochondrial disease(HSD10MD)

MedGen UID:
781653
Concept ID:
C3266731
Disease or Syndrome
Synonyms: 17 beta-hydroxysteroid dehydrogenase type 10 deficiency; 17-beta-hydroxysteroid dehydrogenase X deficiency; 2-methyl-3-hydroxybutyric aciduria; 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency; 2M3HBA; 3-hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency; 3H2MBD deficiency; Chorioathetosis with Mental Retardation and Abnormal Behavior; HSD10 deficiency; HSD10 disease; HSD10MD; HSD17B10 DEFICIENCY; Hydroxyacyl-CoA dehydrogenase II deficiency
SNOMED CT: 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (801000124108); 2-methyl-3-hydroxybutyric aciduria (791000124107); HSD10 disease (791000124107)
Modes of inheritance:
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Source: Orphanet
A mode of inheritance that is observed for dominant traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked dominant disorders tend to manifest very severely in affected males. The severity of manifestation in females may depend on the degree of skewed X inactivation.
 
Gene (location): HSD17B10 (Xp11.22)
 
Monarch Initiative: MONDO:0010327
OMIM®: 300438
Orphanet: ORPHA391417

Definition

HSD10 mitochondrial disease (HSD10MD) most commonly presents as an X-linked neurodegenerative disorder with highly variable severity and age at onset ranging from the neonatal period to early childhood. The features are usually multisystemic, consistent with mitochondrial dysfunction. Some affected males have a severe infantile form associated with cardiomyopathy that may result in death in early childhood, whereas other rare patients may have juvenile onset or even atypical presentations with normal neurologic development. More severely affected males show developmental regression in infancy or early childhood, often associated with early-onset intractable seizures, progressive choreoathetosis and spastic tetraplegia, optic atrophy or retinal degeneration resulting in visual loss, and mental retardation. Heterozygous females may show non-progressive developmental delay and intellectual disability, but may also be clinically normal. Although the diagnosis can be aided by the observation of increased urinary levels of metabolites of isoleucine breakdown (2-methyl-3 hydroxybutyrate and tiglylglycine), there is not a correlation between these laboratory features and the phenotype. In addition, patients do not develop severe metabolic crises in the neonatal period as observed in other organic acidurias, but may show persistent lactic acidosis, most likely reflecting mitochondrial dysfunction (summary by Rauschenberger et al., 2010; Zschocke, 2012). In a review of this disorder, Zschocke (2012) noted that although it was originally thought to be an inborn error of branched-chain fatty acid and isoleucine metabolism resulting from decreased HSD17B10 dehydrogenase activity (HSD17B10 'deficiency'), subsequent studies have shown that the HSD17B10 gene product has additional functions and also acts as a component of the mitochondrial RNase P holoenzyme, which is involved in mitochondrial tRNA processing and maturation and ultimately mitochondrial protein synthesis. The multisystemic features of HSD10MD most likely result from the adverse effect of HSD17B10 mutations on mitochondrial function, rather than from the effects on the dehydrogenase activity (see PATHOGENESIS). [from OMIM]

Additional description

From MedlinePlus Genetics
HSD10 disease is a disorder that affects the nervous system, vision, and heart. It is typically more severe in males than in females. Most affected males have a form of HSD10 disease in which early development seems normal, followed by a stage in which affected individuals rapidly lose skills they have acquired. This developmental regression often occurs between the ages of 1 and 2 and results in severe intellectual disability and loss of communication skills and motor skills such as sitting, standing, and walking. This form of the disorder is referred to as the infantile type. Less commonly, affected males have severe neurological problems from birth and never develop motor skills. This form is called the neonatal type. Males with the infantile or neonatal type frequently have weak muscle tone (hypotonia), recurrent seizures (epilepsy), and vision loss that gradually gets worse. Weakening of the heart muscle (cardiomyopathy) also occurs and is a common cause of death in males with severe HSD10 disease. Many affected males do not survive beyond early childhood.

Females with HSD10 disease may have developmental delay, learning problems, or intellectual disability, but they do not experience developmental regression. Some affected females have additional features of this condition, such as epilepsy, movement problems, and hearing loss. Affected females appear to have a normal life expectancy.  https://medlineplus.gov/genetics/condition/hsd10-disease

Clinical features

From HPO
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.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Behavior or an act aimed at harming a person, animal, or physical property (e.g., acts of physical violence; shouting, swearing, and using harsh language; slashing someone's tires).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
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 characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Choreoathetosis
MedGen UID:
39313
Concept ID:
C0085583
Disease or Syndrome
Involuntary movements characterized by both athetosis (inability to sustain muscles in a fixed position) and chorea (widespread jerky arrhythmic movements).
Agitation
MedGen UID:
88447
Concept ID:
C0085631
Sign or Symptom
A state of extreme restlessness and excessive motor activity is associated with mental distress or a feeling of inner tension.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
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.
Progressive neurologic deterioration
MedGen UID:
381506
Concept ID:
C1854838
Finding
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.
Restlessness
MedGen UID:
854457
Concept ID:
C3887611
Sign or Symptom
A state of unease is characterized by diffuse motor activity or motion, which is subject to limited control, nonproductive, or disorganized behavior.
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
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.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
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.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Elevated circulating tiglylglycine concentration
MedGen UID:
1815052
Concept ID:
C5706146
Finding
Concentration of tiglylglycine in the blood circulation above the upper limit of normal.
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.
Retinal degeneration
MedGen UID:
48432
Concept ID:
C0035304
Finding
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells.
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).
Abnormal mitochondrial morphology
MedGen UID:
863087
Concept ID:
C4014650
Finding
Any structural anomaly of the mitochondria.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHSD10 mitochondrial disease

Professional guidelines

PubMed

Aitken L, Benek O, McKelvie BE, Hughes RE, Hroch L, Schmidt M, Major LL, Vinklarova L, Kuca K, Smith TK, Musilek K, Gunn-Moore FJ
Molecules 2019 Jul 29;24(15) doi: 10.3390/molecules24152757. PMID: 31362457Free PMC Article
Hroch L, Guest P, Benek O, Soukup O, Janockova J, Dolezal R, Kuca K, Aitken L, Smith TK, Gunn-Moore F, Zala D, Ramsay RR, Musilek K
Bioorg Med Chem 2017 Feb 1;25(3):1143-1152. Epub 2016 Dec 27 doi: 10.1016/j.bmc.2016.12.029. PMID: 28082069
Hroch L, Benek O, Guest P, Aitken L, Soukup O, Janockova J, Musil K, Dohnal V, Dolezal R, Kuca K, Smith TK, Gunn-Moore F, Musilek K
Bioorg Med Chem Lett 2016 Aug 1;26(15):3675-8. Epub 2016 May 30 doi: 10.1016/j.bmcl.2016.05.087. PMID: 27287370

Recent clinical studies

Diagnosis

Waters PJ, Lace B, Buhas D, Gravel S, Cyr D, Boucher RM, Bernard G, Lévesque S, Maranda B
Mol Genet Genomic Med 2019 Dec;7(12):e1000. Epub 2019 Oct 26 doi: 10.1002/mgg3.1000. PMID: 31654490Free PMC Article

Prognosis

Waters PJ, Lace B, Buhas D, Gravel S, Cyr D, Boucher RM, Bernard G, Lévesque S, Maranda B
Mol Genet Genomic Med 2019 Dec;7(12):e1000. Epub 2019 Oct 26 doi: 10.1002/mgg3.1000. PMID: 31654490Free PMC Article

Clinical prediction guides

Waters PJ, Lace B, Buhas D, Gravel S, Cyr D, Boucher RM, Bernard G, Lévesque S, Maranda B
Mol Genet Genomic Med 2019 Dec;7(12):e1000. Epub 2019 Oct 26 doi: 10.1002/mgg3.1000. PMID: 31654490Free PMC Article

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