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Ann Neurol. 2020 Apr;87(4):568-583. doi: 10.1002/ana.25685. Epub 2020 Feb 8.

Novel Recessive TNNT1 Congenital Core-Rod Myopathy in French Canadians.

Author information

1
Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec, Canada.
2
Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA.
3
Department of Pathology, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.
4
Department of Pathology, Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec, Canada.
5
Department of Neurology, Hôpital Hôtel-Dieu de Lévis, Lévis, Quebec, Canada.
6
Department of Neurology, Hôpital de l'Enfant Jésus, Université Laval, Quebec City, Quebec, Canada.
7
Department of Neurosciences, University of California, San Diego, San Diego, CA.
8
Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
9
Neuromuscular Disease Clinic, Centre Intégré Universitaire de Santé et de Services Sociaux du Saguenay-Lac-Saint-Jean, Jonquière, Quebec, Canada.
10
Department of Neurosciences, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
11
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
12
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
13
Department of Child Neurology, Centre Hospitalier de l'Université Laval et Centre Mère-Enfant Soleil, Université Laval, Quebec City, Quebec, Canada.

Abstract

OBJECTIVE:

Recessive null variants of the slow skeletal muscle troponin T1 (TNNT1) gene are a rare cause of nemaline myopathy that is fatal in infancy due to respiratory insufficiency. Muscle biopsy shows rods and fiber type disproportion. We report on 4 French Canadians with a novel form of recessive congenital TNNT1 core-rod myopathy.

METHODS:

Patients underwent full clinical characterization, lower limb magnetic resonance imaging (MRI), muscle biopsy, and genetic testing. A zebrafish loss-of-function model using morpholinos was created to assess the pathogenicity of the identified variant. Wild-type or mutated human TNNT1 mRNAs were coinjected with morpholinos to assess their abilities to rescue the morphant phenotype.

RESULTS:

Three adults and 1 child shared a novel missense homozygous variant in the TNNT1 gene (NM_003283.6: c.287T > C; p.Leu96Pro). They developed from childhood very slowly progressive limb-girdle weakness with rigid spine and disabling contractures. They suffered from restrictive lung disease requiring noninvasive mechanical ventilation in 3 patients, as well as recurrent episodes of rhabdomyolysis triggered by infections, which were relieved by dantrolene in 1 patient. Older patients remained ambulatory into their 60s. MRI of the leg muscles showed fibrofatty infiltration predominating in the posterior thigh and the deep posterior leg compartments. Muscle biopsies showed multiminicores and lobulated fibers, rods in half the patients, and no fiber type disproportion. Wild-type TNNT1 mRNA rescued the zebrafish morphants, but mutant transcripts failed to do so.

INTERPRETATION:

This study expands the phenotypic spectrum of TNNT1 myopathy and provides functional evidence for the pathogenicity of the newly identified missense mutation. ANN NEUROL 2020;87:568-583.

PMID:
31970803
PMCID:
PMC7078025
[Available on 2021-04-01]
DOI:
10.1002/ana.25685

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