Childhood onset dystonia, chorea or related movement disorder

Gene: NDUFA2

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 19 Jun 2022, 11:23 p.m. | Last Modified: 19 Jun 2022, 11:23 p.m.

Panel Version: 1.237

Green List (high evidence)

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - at least three unrelated cases presenting a movement phenotype following a period of regression.

Created: 3 Aug 2020, 12:59 p.m. | Last Modified: 3 Aug 2020, 12:59 p.m.

Panel Version: 1.6

Associated with Mitochondrial complex I deficiency, nuclear type 13 in OMIM, but not in G2P.

PMID: 28857146 (2018) - Two unrelated cases. In a 12-year-old female with cystic leukodystrophy, WES revealed a homozygous variant in NDUFA2 (c.134A>C, p.Lys45Thr). She exhibited developmental regression until age 12 months, followed by stabilisation. Her examination was significant for severe spasticity and other upper motor neuron signs, predominantly in the legs, with cerebellar features and generalised dystonia.
In the second leukoencephalopathy patient, compound heterozygous variants were identified in NDUFA2 ([c.134A>C, p.Lys45Thr];[c.225del, p.Asn76Metfs*4]). The patient presented at 8 months with fever, failure to thrive and developmental regression. Her examination was significant for severe irritability, no purposeful hand movements, and upper motor neuron signs. At 4-years-old she was microcephalic, could speak in short sentences and walked with a walker, but used a wheelchair for long distances.

PMID: 32154054 (2020) - Homozygous missense variant (c.170A>C, p.Glu57Ala) identified in a 4-year-old female presenting with cavitating and tigroid‐like leukoencephalopathy. She was able to walk independently at 17 months. By 20 months, she experienced a slow regression of both motor and verbal skills without any apparent trigger, but subsequently regained limited motor and language skills over the following months.

Created: 3 Aug 2020, 12:16 p.m. | Last Modified: 3 Aug 2020, 12:16 p.m.

Panel Version: 1.4

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial complex I deficiency, nuclear type 13, 618235

Publications

• 28857146
• 32154054

Red List (low evidence)

Red List (low evidence)

PMID 18513682 describes a single patient with Leigh Syndrome (but no mention of dystonia). PMID 28857146 describes a further patient with leukoencephalopathy. PMID 27159321 found a VUS in patient with white matter abnormality

Created: 9 Jul 2019, 3:59 p.m. | Last Modified: 9 Jul 2019, 3:59 p.m.

Panel Version: 0.10