CHCHD10-Related Disorders

Disease Overview

Summary

CHCHD10-related disorders are a group of adult-onset neurodegenerative conditions associated with a change (disease-causing variant) in the CHCHD10 gene.¹ Variants in this gene can cause mitochondrial myopathy, amyotrophic lateral sclerosis, frontotemporal dementia, late-onset spinal motor neuronopathy, axonal Charcot-Marie-Tooth neuropathy and cerebellar ataxia.

While not everyone with these conditions has a CHCHD10 gene variant, each disorder listed above has been linked to variants in CHCHD10. A person can be diagnosed with one of these disorders, or more than one. Therefore, when someone has a variant in the CHCHD10 gene, doctors need to look for any of the described related health issues.¹

People with CHCHD10-related disorders have a range of different symptoms, some of which can include muscle weakness and atrophy, sensory abnormalities and cognitive decline. Treatment is disease-specific and may include physical, occupational, speech and respiratory therapy, in addition to certain medications.

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Subdivisions

• CHCHD10-related frontotemporal dementia/amyotrophic lateral sclerosis or frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis 2 (FTD-ALS2)
• autosomal dominant isolated mitochondrial myopathy (also known as myopathy, isolated mitochondrial, autosomal dominant [IMMD] and as autosomal dominant mitochondrial myopathy with exercise intolerance)
• Jokela type of spinal muscular atrophy (also known as spinal muscular atrophy, Jokela type [SMAJ]) or lower motor neuron syndrome with late-adult onset or as late-onset spinal motor neuronopathy (LOSMoN)
• CHCHD10-related axonal Charcot-Marie-Tooth neuropathy
• CHCHD10-related cerebellar ataxia

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Signs & Symptoms

The signs and symptoms of CHCHD10-related disorders are identical to those seen in people who have the associated disorders but do not have CHCHD10 gene variants. These conditions may occur together or appear on their own. Signs and symptoms may include:^{1,2,3,4,5,6,7}

Mitochondrial myopathy: People with this form of the condition may present with:

• Exercise intolerance
• Muscle weakness, especially in the shoulders/hips (proximal), trunk (axial), or face
• Droopy eyelids (ptosis) and muscle wasting (amyotrophy)
• Hearing loss in some people

It may have an early onset (during childhood) with muscle weakness before age 10, sometimes with short stature, or a late onset (adulthood) where muscle weakness appears later and can be associated with nerve and balance problems.

Amyotrophic lateral sclerosis (ALS): Symptoms of CHCHD10-related ALS may include:

• Muscle weakness and stiffness, usually starting in arms or legs
• Trouble swallowing or speaking (bulbar involvement) in more advanced stages
• Muscle twitching (fasciculations)
• Breathing problems eventually, which can be life-threatening

Onset is usually in the early 50s (range 25–75 years). People often live 5–10 years, but this can vary widely. Sometimes this form of the disease appears together with frontotemporal dementia (see below).

Frontotemporal dementia (FTD) which may include the following:

• Behavior changes such as acting without restraint, loss of motivation, neglecting personal care
• Language problems such as difficulty finding words or understanding conversations
• Personality changes such as becoming obsessive, restless, or showing unusual eating/drinking habits
• Movement problems like slowed movements (bradykinesia) or stiffness

Symptoms usually start between the ages of 50 and 67. The course can last from 4 to 27 years.

Spinal muscular atrophy, Jokela type (SMAJ) characterized by:

• Muscle cramps and twitching in legs
• Slowly worsening leg weakness but normal breathing
• Reduced reflexes (for example, knee‐jerk)
• Mild swallowing difficulty in a few people, appearing much later

The onset of SMAJ symptoms is usually between ages 30 and 73 (average early 40s). Progression is very slow; most people are able to continue walking for decades.

Axonal Charcot-Marie-Tooth neuropathy (CMT2) characterized by:

• Gradual weakness in lower legs, then hands
• Muscle wasting (especially in calves)
• Loss of reflexes
• Numbness or tingling (reduced vibration or cold sensation)

Onset from 30 to 56 years (average mid-40s). Slow progression; no effects on breathing or thinking.

Cerebellar ataxia which may include the following:

• Unsteady walking, especially on stairs or turning quickly
• Slurred speech (dysarthria) and later trouble swallowing
• Eye movement problems (nystagmus, slow eye jumps)
• Poor coordination (dysmetria) and trouble doing rapid alternating movements

Usually appears in the 50s or 60s.

As commented before, people can have isolated forms of the these disorders or a combination of symptoms of the different disorders.

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Causes

CHCHD10-related disorders are caused by variants in the CHCHD10 gene. This gene provides instructions for making mitochondrial proteins that play important roles in neuron development and function.⁸ These proteins help with mitochondrial fusion, fission and gene expression, which are important for maintaining healthy cell mitochondria.⁹ Variants in CHCHD10 can inhibit the proper formation of these mitochondrial proteins and lead to motor neuron diseases and neurological disorders.¹⁰

One key role of the mitochondria is to turn glucose (sugar) into ATP (energy for the cell). CHCHD10 variants have been shown to specifically impair the last step in this process called oxidative phosphorylation.¹¹

CHCHD10 is also implicated in cell death (apoptosis), synaptic plasticity and lipid metabolism, though the mechanisms for these activities are unclear.⁹

Inheritance

CHCHD10-related disorders follow an autosomal dominant inheritance pattern. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

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Affected populations

CHCHD10-related disorders do not preferentially affect any one ethnic group, as they have been observed in a French family¹², a Puerto Rican family¹³, two German families¹⁴, three American families¹⁵ and a man from Catalonia, Spain¹¹, among others. The overall prevalence is rare, such that for any given diagnosis, less than 5% of affected individuals will have a variant in CHCHD10. The only exception is spinal muscular atrophy, Jokela type (SMAJ), which is more frequently seen in people of Finnish descent.¹⁶

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Disorders with Similar Symptoms

All of the conditions related to the CHCHD10 gene variants can have causes other than variants in the CHCHD10 gene. Because the symptoms are identical, regardless of the specific cause, the differential diagnosis needs to include genetic testing.

• Mitochondrial myopathy is a symptom of mitochondrial diseases, or disorders that arise from functional and structural alterations of mitochondria caused by variants in genes that code for mitochondrial proteins. Mitochondrial disease occurs in more than 1 in 5,000 adults, making it one of the most common groups of genetic diseases.¹⁷ Mitochondrial myopathy is associated with proximal muscle weakness.²
• Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that impairs voluntary muscle movements. Symptoms can begin in the arms/legs (limb-onset) or face/throat (bulbar-onset) and include muscle weakness, slurred speech and difficulty swallowing/breathing. Over 95% of people with ALS have abnormal accumulation of a protein called TDP-43, while the other 5% show abnormal accumulation of different proteins called SOD1 and FUS.¹⁸ The lifetime risk for a person to develop ALS is estimated to be 1 in 350 (males) and 1 in 400 (females).¹⁹ ALS can occur by itself or in combination with FTD (also known as ALS-FTD). The exact mechanism of how CHCHD10 variants cause ALS is currently being studied and may be far less prevalent than previously thought.²⁰
• Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder that affects the frontal and temporal brain regions.⁶ Symptoms include extreme behavioral changes (inappropriate social behavior, loss of inhibition, decline in personal hygiene and more) and language impairment (difficulty speaking and understanding language).²¹ There are three subtypes, which include semantic dementia, progressive nonfluent aphasia and behavioral variant. Similar to ALS, FTD shows abnormal accumulation of TDP-43 in 45% of cases.¹⁸ FTD can occur by itself or in combination with ALS (also known as ALS-FTD).
• Spinal muscular atrophy (SMA) due to different causes, which may have similar symptoms to SMA Jokela type, especially types of SMA that start later in life.²²
• Axonal Charcot-Marie-Tooth neuropathy is part of a larger group of inherited peripheral neuropathies and is characterized by progressive sensory and/or motor dysfunction that travels from the distal lower limbs to the distal upper limbs. It is theorized to result from progressive, length-dependent loss of axons, motor and sensory complications in the feet and lower legs and impaired balance.²³
• Cerebellar ataxia is a group of disorders characterized by abnormal gait and balance, fine motor complications and abnormalities of eye movement and speech due to changes or dysfunction of the cerebellum.²⁴ Ataxia can present acutely, such as in the case of damage to the cerebellum, or gradually as a result of abnormal development of the cerebellum as in the case of CHCHD10 related cerebellar ataxia.

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Diagnosis

Diagnosis of this disorder is only confirmed through molecular genetic testing to confirm a disease-causing (pathogenic) variant in CHCHD10 gene. Testing may be considered in an individual with any combination of mitochondrial myopathy, amyotrophic lateral sclerosis, frontotemporal dementia, late-onset spinal motor neuronopathy, or axonal Charcot-Marie-Tooth neuropathy.¹ Individuals with a family history of these conditions should also be considered for evaluation.

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Standard Therapies

Given the wide range of symptoms for CHCHD10-related disorders, treatment is specific to the diagnosis, symptoms and severity. Treatment may include:

• physical therapy to help with movement and strength
• occupational therapy to support daily activities
• speech and language therapy for communication and swallowing issues
• respiratory therapy for breathing support

Medications may also help manage symptoms. Care from a team of specialized doctors is recommended.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

1. Saadi SAEM, Chaussenot A, Bannwarth S, Cécile Rouzier, Véronique Paquis-Flucklinger. CHCHD10-Related Disorders. Nih.gov. Published May 27, 2021. Accessed July 10, 2025. https://www.ncbi.nlm.nih.gov/books/NBK304142/
2. Lu JQ, Tarnopolsky MA. Mitochondrial neuropathy and neurogenic features in mitochondrial myopathy. Mitochondrion. 2021;56:52-61. doi:https://doi.org/10.1016/j.mito.2020.11.005
3. Meyer T. [Amyotrophic lateral sclerosis (ALS) – diagnosis, course of disease and treatment options]. Deutsche Medizinische Wochenschrift (1946). 2021;146(24-25):1613-1618. doi:https://doi.org/10.1055/a-1562-7882
4. Klein CJ. Charcot-Marie-Tooth Disease and Other Hereditary Neuropathies. CONTINUUM: Lifelong Learning in Neurology. 2020;26(5):1224-1256. doi:https://doi.org/10.1212/con.0000000000000927
5. Bang J, Spina S, Miller BL. Frontotemporal dementia. The Lancet. 2015;386(10004):1672-1682. doi:https://doi.org/10.1016/s0140-6736(15)00461-4
6. Mayo Clinic. Frontotemporal Dementia – Symptoms and Causes. Mayo Clinic. Published November 28, 2023. https://www.mayoclinic.org/diseases-conditions/frontotemporal-dementia/symptoms-causes/syc-20354737
7. Pedroso JL, Vale TC, Braga-Neto P, et al. Acute cerebellar ataxia: differential diagnosis and clinical approach. Arquivos de Neuro-Psiquiatria. 2019;77(3):184-193. doi:https://doi.org/10.1590/0004-282×20190020
8. Harjuhaahto S, Rasila TS, Molchanova SM, et al. ALS and Parkinson’s disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons. Neurobiology of disease. 2020;141:104940-104940. doi:https://doi.org/10.1016/j.nbd.2020.104940
9. Jiang T, Wang Y, Wang X, Xu J. CHCHD2 and CHCHD10: Future therapeutic targets in cognitive disorder and motor neuron disorder. Frontiers in Neuroscience. 2022;16. doi:https://doi.org/10.3389/fnins.2022.988265
10. Zhou W, Ma D, Tan EK. Mitochondrial CHCHD2 and CHCHD10: Roles in Neurological Diseases and Therapeutic Implications. The Neuroscientist. 2019;26(2):170-184. doi:https://doi.org/10.1177/1073858419871214
11. Bannwarth S, Ait-El-Mkadem S, Chaussenot A, et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain. 2014;137(8):2329-2345. doi:https://doi.org/10.1093/brain/awu138
12. Genin EC, Plutino M, Bannwarth S, et al. CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis. EMBO Molecular Medicine. 2016;8(1):58-72. doi:https://doi.org/10.15252/emmm.201505496
13. Ajroud-Driss S, Fecto F, Ajroud K, et al. Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy. neurogenetics. 2014;16(1):1-9. doi:https://doi.org/10.1007/s10048-014-0421-1
14. Müller K, Andersen PM, Hübers A, et al. Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. Brain. 2014;137(12):e309-e309. doi:https://doi.org/10.1093/brain/awu227
15. Johnson JO, Glynn SM, Gibbs JR, et al. Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis. Brain. 2014;137(12):e311-e311. doi:https://doi.org/10.1093/brain/awu265
16. Penttilä S, Jokela M, Saukkonen AM, et al. CHCHD10 mutations and motor neuron disease: the distribution in Finnish patients. Journal of Neurology, Neurosurgery & Psychiatry. 2016;88(3):272-277. doi:https://doi.org/10.1136/jnnp-2016-314154
17. Ng YS, Turnbull DM. Mitochondrial disease: genetics and management. Journal of Neurology. 2016;263(1):179-191. doi:https://doi.org/10.1007/s00415-015-7884-3
18. Brown AL, Wilkins OG, Keuss MJ, et al. TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. Nature. 2022;603(7899):131-137. doi:https://doi.org/10.1038/s41586-022-04436-3
19. Ryan M, Heverin M, McLaughlin RL, Hardiman O. Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis. JAMA Neurology. 2019;76(11). doi:https://doi.org/10.1001/jamaneurol.2019.2044
20. CHCHD10 variants in amyotrophic lateral sclerosis: Where is the evidence?. Annals of neurology. 2018;84(1):110-116. doi:https://doi.org/10.1002/ana.25273
21. Humphrey J. RNA Dysregulation in Models of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. University College London; 2019.
22. Nadja Ratia, Palu E, Lantto H, et al. Lowered oxidative capacity in spinal muscular atrophy, Jokela type; comparison with mitochondrial muscle disease. Frontiers in Neurology. 2023;14. doi:https://doi.org/10.3389/fneur.2023.1277944
23. McCray BA, Scherer SS. Axonal Charcot-Marie-Tooth Disease: from Common Pathogenic Mechanisms to Emerging Treatment Opportunities. Neurotherapeutics. 2021;18(4):2269-2285. doi:https://doi.org/10.1007/s13311-021-01099-2
24. Rosenthal LS. Neurodegenerative Cerebellar Ataxia. Continuum (Minneapolis, Minn). 2022;28(5):1409-1434. doi:https://doi.org/10.1212/CON.0000000000001180

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