Possible mitochondrial disorder - nuclear genes

Gene: TIMM8A

Green List (high evidence)

Comment on mode of inheritance: As there are at least 3 unrelated symptomatic females reported in literature with heterozygous TIMM8A variants, the MOI should be changed to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males).

Created: 22 Jul 2026, 1 p.m. | Last Modified: 22 Jul 2026, 1 p.m.

Panel Version: 5.10

PMID: 40597358 Ventura et al., 2025
Report of a 16yo male with 6-year history of progressive dystonia, motor coordination difficulties, and iron deposits in the basal ganglia detected by brain MRI; no hearing loss. WES detected a hemizygous TIMM8A variant c.98_101dupAGCA.
The variant was inherited from a heterozygous mother, 43yo, who had recurrent muscle spasms - confirmed generalized dystonia, particularly affecting the upper extremities and cervical muscles. Maternal uncle showed motor clumsiness and finger spasms in childhood. Neither had hearing loss or visual impairment.

PMID: 22736418 Ha et al., 2012
Report of a female proband (kindred B) heterozygous for a TIMM8A variant c.127del, p.Cys43Valfs*22. She presented with deafness (onset in early 40s) and dystonia (initially in right upper limb) with onset in mid 40s. Dystonia progressed to oromandibular, upper limbs, and lower limbs. Cognitive decline was noted in her 50s.

PMID: 11601506 Swerdlow & Wooten, 2001
Kindred with Mohr-Tranebjaerg syndrome. Proband is a 30yo male with congenital deafness, and generalised dystonia starting around 28yo. Proband's mother reported head shaking, chronic neck muscle pain, and writer's cramp since age 25yrs. 1 female sibling of the proband was unaffected, while the other reported head shaking and writer's cramp with onset in late teens / early 20s. Affected patients harboured TIMM8A (old name DDP1) c.108del.

Created: 22 Jul 2026, 1 p.m. | Last Modified: 22 Jul 2026, 1 p.m.

Panel Version: 5.10

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Mohr-Tranebjaerg syndrome, OMIM:304700; deafness dystonia syndrome, MONDO:0010578

Publications

• 11601506
• 22736418
• 40597358

PMID: 32820032 (2020) - Animal mouse model with a hemizygous variant (p.I23fs49X) in Timm8a1, recapitulated features of deafness-dystonia-optic neuronopathy (DDON) syndrome, associated with this gene. Mutant male mice exhibited hearing impairment, cognitive decline, and some age-dependant alteration in motor coordination and balance. Abnormal mitochondrial morphology was detected in several brain regions of mutant mice using electron microscopy.

Created: 2 Sep 2020, 2:09 p.m. | Last Modified: 2 Sep 2020, 2:09 p.m.

Panel Version: 1.16

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Publications

• 32820032

Green List (high evidence)

Initial gene list and info collated by Carl Fratter (Oxford University Hospitals NHS Trust) January 2019 on behalf of the GMS Mitochondrial specialist test group.

Created: 4 Feb 2019, 1:36 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Mohr-Tranebjaerg syndrome, 304700

Green List (high evidence)

Comment on mode of inheritance: Hemizygous indicated for both disorders in G2P. XLR indicated for Mohr-Tranebjaerg syndrome, and XL for Jensen syndrome.

Created: 2 Mar 2016, 2:11 p.m.

Comment on list classification: Promoted from red to green due to expert review, and it is a "Both DD and IF" gene on G2P for both MOHR-TRANEBJAERG SYNDROME and JENSEN SYNDROME.

Created: 2 Mar 2016, 2:09 p.m.

This gene was submitted as "DDP" in the expert list, which is likely to correspond to this HGNC-approved symbol.

Created: 1 Jul 2015, 10:43 a.m.