Clinical characteristics.

CHCHD10-related disorders are characterized by a spectrum of adult-onset neurologic phenotypes that can include:

• Mitochondrial myopathy (may also be early onset): weakness, amyotrophy, exercise intolerance
• Amyotrophic lateral sclerosis (ALS): progressive degeneration of upper motor neurons and lower motor neurons
• Frontotemporal dementia (FTD): slowly progressive behavioral changes, language disturbances, cognitive decline, extrapyramidal signs
• Late-onset spinal motor neuronopathy (SMA, Jokela type): weakness, cramps, and/or fasciculations; areflexia
• Axonal Charcot-Marie-Tooth neuropathy: slowly progressive lower-leg muscle weakness and atrophy, small hand muscle weakness, loss of tendon reflexes, sensory abnormalities
• Cerebellar ataxia: gait ataxia, kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements), dysarthria/dysphagia, nystagmus, cerebellar oculomotor disorder

Because of the recent discovery of CHCHD10-related disorders and the limited number of affected individuals reported to date, the natural history of these disorders (except for SMAJ caused by the p.Gly66Val pathogenic variant) is largely unknown.

Diagnosis/testing.

The diagnosis is established when a heterozygous CHCHD10 pathogenic variant is detected in an individual with one or more characteristic clinical findings.

Management.

Treatment of manifestations: Adequate nutrition and weight maintenance are essential. Appropriate bracing and stretching can minimize joint contractures, which are often painful and can interfere with caregiving. Those with weakness benefit from assistance with ambulation and posture. Management of ALS, FTD, SMA, and cerebellar ataxia is the same as for other causes of these disorders.

Surveillance: Regular evaluations to detect manifestations that can occur with time including neurologic deficits, psychiatric abnormalities, impaired respiratory function, and sensorineural hearing loss.

Agents/circumstances to avoid: Baclofen (used to treat spasticity) can sometimes worsen muscle weakness; some drugs used to treat the behavioral manifestations of FTD may worsen dysarthria, dysphagia, and/or respiratory weakness.

Genetic counseling.

CHCHD10-related disorders are inherited in an autosomal dominant manner. Many individuals diagnosed with a CHCHD10-related disorder have an affected parent. The proportion of probands with a CHCHD10-related disorder caused by a de novo pathogenic variant is unknown. Each child of an individual with a CHCHD10-related disorder has a 50% chance of inheriting the CHCHD10 pathogenic variant. Because significant clinical heterogeneity is observed within families, it is impossible to accurately predict the age at onset and manifestations that will develop in individuals who inherit a CHCHD10 pathogenic variant. Once the CHCHD10 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for a CHCHD10-related disorder and preimplantation genetic testing are possible.

Suggestive Findings

A CHCHD10-related disorder should be suspected in an individual with clinical findings of a mitochondrial myopathy, amyotrophic lateral sclerosis, frontotemporal dementia, late-onset spinal motor neuronopathy, or axonal Charcot-Marie-Tooth neuropathy, especially when the family history of these diverse phenotypes is consistent with autosomal dominant inheritance.

Establishing the Diagnosis

The diagnosis of a CHCHD10-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in CHCHD10 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous CHCHD10 variant of uncertain significance does not establish or rule out the diagnosis.

Because a CHCHD10-related disorder may be associated with a number of different phenotypes (even within a single family) and is indistinguishable from these same phenotypes with other known or unknown causation, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of CHCHD10, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• A phenotype-specific multigene panel that includes CHCHD10 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

The phenotypic spectrum of CHCHD10-related disorders is broad and can include any of the following alone or in any combination: mitochondrial myopathy, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), late-onset spinal motor neuronopathy, and axonal Charcot-Marie-Tooth neuropathy. Cerebellar ataxia may also be found in combination with these disorders, but not as the sole neurologic manifestation.

To date, approximately 100 individuals have been identified with a pathogenic variant in CHCHD10 [Bannwarth et al 2014, Ajroud-Driss et al 2015, Auranen et al 2015, Penttilä et al 2015]. The following description of the phenotypes associated with this condition is based on these reports. It should be noted that other individuals have been reported with CHCHD10 variants for which the pathogenicity is controversial and there is a need for more studies to classify them as pathogenic or not [Tazelaar et al 2018].

Mitochondrial myopathy may present with exercise intolerance; proximal, axial, and/or facial muscle weakness; ptosis; and amyotrophy. Deafness may also be observed.

• Early onset. In a Puerto Rican family, affected individuals had myopathy (appearing in the first decade of life) and short stature [Ajroud-Driss et al 2015].
• Late onset. In a French family, affected individuals had late-onset myopathy with motor neuron disease, FTD, and cerebellar ataxia [Bannwarth et al 2014].

Amyotrophic lateral sclerosis (ALS). CHCHD10-related ALS and ALS of other causes (see ALS Overview) are clinically indistinguishable, including in male-to-female ratio, age of onset, symptom distribution, and severity of disease. Most individuals with CHCHD10-related ALS meet El Escorial criteria for ALS [Brooks et al 2000] and have both UMN and LMN involvement. Within a family, clinical variability is considerable, especially regarding age of onset and longevity.

• The ALS may occur by itself or in combination with FTD (referred to as FTD-ALS).
• Onset. Mean age of onset is 53 years (age range 25-75 years). Upper limb involvement is more frequent at onset of ALS phenotype; bulbar involvement is more predominant at onset in the FTD-ALS phenotype.
• Progression. Bulbar dysfunction (atrophy of facial and masticatory muscles, perioral fasciculations, and severe dysphagia leading to frequent aspiration) become prominent in the final stages of the disease. Affected individuals eventually develop respiratory failure, which is the main cause of death. Mean disease duration prior to death is 8.6 years (range 2-17 years).

Frontotemporal dementia (FTD) is a presenile dementia affecting the frontal and temporal cortex and some subcortical nuclei. Clinical presentation is variable. Affected individuals may have slowly progressive behavioral changes, cognitive decline with language disturbance, and/or extrapyramidal signs.

• Onset and duration of disease. In individuals with CHCHD10-related FTD, symptoms start between ages 50 and 67 years. Disease duration is usually between four and 27 years.
• Behavioral changes. Disinhibition and loss of initiative are the most common presenting symptoms. Affected individuals lose interest in their environment and neglect their personal hygiene. Obsessive-compulsive behavior and delusions or hallucinations are early clinical features in some. Roaming, restlessness, verbal aggressiveness, hyperorality (including alcohol abuse), and financial mismanagement are frequently seen [Foster et al 1997, Bird et al 1999].
  Persecutory delusions and visual or auditory hallucinations, which occur rarely in FTD in general, are not reported in individuals with CHCHD10-related FTD.
• Cognitive decline. Word-finding difficulties and semantic paraphasias in conversational speech are common early findings. Orientation in time and place, visuo-constructive functions, and short-term memory remain intact initially. Executive functions, attention, concentration, and abstract reasoning ability become impaired in all affected individuals. Language comprehension remains relatively preserved over the course of the disease. Perseveration, repetitive utterances, and echolalia lead to mutism after several years [Foster et al 1997].
• Extrapyramidal signs. Affected individuals may show parkinsonian signs including decreased facial expression, bradykinesia, postural instability, and rigidity without resting tremor.
• Neuroimaging. Findings can include the following:
  • Frontal and/or temporal atrophy on brain CT or MRI
  • Decrease of cerebral perfusion anteriorly (single-photon emission computed tomography [SPECT])
  • Frontotemporal hypometabolism (positron emission tomography with ¹⁸F-fluorodeoxyglucose [FDG-PET])
  • Reduced striatal uptake of ¹⁸F-fluoro-L-dopa

Spinal motor neuronopathy

• Spinal motor neuronopathy phenotype in CHCHD10-related disorders (also known as spinal muscular atrophy, Jokela type or SMAJ) is characterized by cramps and fasciculations, slowly progressive and predominantly lower-limb weakness, and diminished or absent deep tendon reflexes; respiratory symptoms are absent.
• Onset and progression. Onset typically occurs between ages 30 and 73 years (mean age 42 years). Progression tends to be slow.
  Mild, non-progressive dysphagia appears later in the disease course in 13% of affected individuals. About half of affected individuals develop mild reduction in sensory nerve amplitudes or reduced vibration sense in the distal lower limbs usually later in the disease course. Affected individuals remain ambulant for several decades after onset [Penttilä et al 2015].

Axonal Charcot-Marie-Tooth neuropathy

• Onset and progression. The onset of symptoms varies from age 30 to 56 years (mean age 44). The typical presenting symptom was slowly progressive lower leg muscle weakness, and small hand muscles were affected later on in the disease. Progression tends to be slow.
• Clinical examination has consistently shown loss of tendon reflexes, muscle weakness, and atrophy. Sensory abnormalities such as loss of sensation for vibration or cold were strong enough to be detected on clinical examination in seven of 12 individuals.
• No signs of upper motor neuron disease, bulbar symptoms, or progressive cognitive issues have been observed.
• Muscular MRI. Lower-limb muscle MRI showed edema or fatty degeneration that was pronounced distally (particularly in calves) and milder in thighs.
• Neurophysiologic findings. ENMG showed chronic motor neuropathy with regeneration; for some, sensory findings (decreased sural nerve action potential amplitude) were evident (consistent with typical CMT2 neuropathy).

Cerebellar ataxia in CHCHD10-related disorders is characterized by ataxia, dysarthria, and eventual deterioration of bulbar functions. Affected individuals have gait difficulties and slurred speech.

• Onset is in the sixth decade. Individuals may first notice balance problems in going down stairs or making sudden turns. In the early stages of disease affected individuals may display brisk deep tendon reflexes, hypermetric saccades, and nystagmus [Schmitz-Hübsch et al 2006]. Mild dysphagia, indicated by choking on food and drink, may also occur early in the disease.
• Progression. As the disease progresses saccadic velocity slows and upgaze palsy develops. Nystagmus often disappears with evolving saccadic abnormalities.
  As the ataxia worsens, other cerebellar signs such as dysmetria, dysdiadochokinesia, and hypotonia become apparent.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

The clinical course of CHCHD10-related disorders is highly variable, even within a family, and is not predictable from the type or location of the pathogenic variant.

Penetrance

Penetrance is difficult to estimate because few unaffected individuals in families with a CHCHD10-related disorder have been genotyped or longitudinally followed for the emergence of symptoms.

Nomenclature

CHCHD10 was previously referred to as C22orf16.

Prevalence

The prevalence of CHCHD10-related disorders is not known at present.

CHCHD10 pathogenic variants have been identified in individuals from different geographic regions including America, Asia, and Europe.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a CHCHD10-related disorder, the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Many individuals benefit from care by a multidisciplinary team that includes a neurologist, specially trained nurses, pulmonologist, speech therapist, physical therapist, occupational therapist, respiratory therapist, nutritionist, psychologist, social worker, and genetic counselor.

Surveillance

Agents/Circumstances to Avoid

The following should be noted:

• Baclofen used to treat spasticity can sometimes worsen muscle weakness.
• Some drugs used to treat the behavioral manifestations of FTD may worsen dysarthria, dysphagia, and/or respiratory weakness.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

CHCHD10-related disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Many individuals diagnosed with a CHCHD10-related disorder have an affected parent.
• A proband with a CHCHD10-related disorder may have the disorder as the result of a de novo CHCHD10 pathogenic variant; however, the proportion of probands who have a de novo pathogenic variant is unknown.
• Clinical examination and molecular genetic testing for the CHCHD10 pathogenic variant identified in the proband are recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The family history of some individuals diagnosed with a CHCHD10-related disorder may appear to be negative because of failure by health care professionals to recognize the disorder in family members and/or milder phenotypic presentation, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because significant clinical heterogeneity is observed within families, it is impossible to accurately predict the age at onset and manifestations that will develop in sibs who inherit a CHCHD10 pathogenic variant [Bannwarth et al 2014].
• If the CHCHD10 pathogenic variant detected in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the CHCHD10 pathogenic variant but are clinically unaffected, sibs of a proband are still presumed to be at increased risk for a CHCHD10-related disorder because of the possibility of age-related penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with a CHCHD10-related disorder has a 50% chance of inheriting the CHCHD10 pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the CHCHD10 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the CHCHD10 pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of a CHCHD10-related disorder, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the CHCHD10 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Note: The clinical course of CHCHD10-related disorders is highly variable and cannot be predicted based on family history or the presence of a pathogenic variant identified on prenatal testing.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors position statement on prenatal testing for adult-onset conditions.

Molecular Pathogenesis

The precise function of CHCHD10 in mitochondria is unclear. Fibroblasts of individuals with p.Ser59Leu variant in CHCHD10 have displayed respiratory chain deficiency, fragmentation of the mitochondrial network, and mitochondrial ultrastructural alterations with loss of cristae [Bannwarth et al 2014]. CHCHD10 interacts with Mitofilin/MIC60, a central component of mitochondrial contact site and cristae organizing system (MICOS) complex, the integrity of which is required for the maintenance of mitochondrial cristae. The p.Ser59Leu variant in human cells leads to MICOS complex disassembly and loss of cristae junctions [Genin et al 2016]. In mice, Chchd10 knockout does not cause disease, indicating that CHCHD10 phenotypes associated with the p.Ser59Leu variant are caused by gain of function of the variant protein rather than by loss of function [Anderson et al 2019].

Knock-in (KI) mice with a punctual pathogenic variant in Chchd10 corresponding to the p.Ser59Leu variant in human CHCHD10 are a relevant model for the disease [Genin et al 2019]. Chchd10^S59L/+ mice appear normal at birth but fail to gain weight normally beginning at age ten weeks. Around age one year, they present a typical mitochondrial myopathy. Their condition worsens rapidly with severe weight loss and tremors and they develop a fatal mitochondrial cardiomyopathy. At the end stage of the disease, around age one year, Chchd10^S59L/+ animals display neuromuscular junction and motor neuron (MN) degeneration with hyperfragmentation of the motor end plate and significant MN loss in lumbar spinal cord. In addition, TDP-43 cytoplasmic aggregates are observed in spinal neurons, corresponding to TDP-43 proteinopathy found in individuals with ALS [Genin et al 2019].

Mechanism of disease causation. From the mouse model, pathogenic variants in CHCHD10 appear to cause disease via a gain-of-function mechanism [Anderson et al 2019].

CHCHD10-specific laboratory technical considerations. The genomic region of CHCHD10, particularly a part of exon 2 (5’ end), may have low-to-moderate coverage using exome sequencing as currently available in the clinical laboratory, potentially making the diagnosis more challenging.

Author Notes

Authors belong to the Department of Medical Genetics and the Reference Center for Rare Diseases on "Mitochondrial Disorders," at the Teaching Hospital of Nice (CHU de Nice) and UCA (Université Côte d'Azur). This reference center is affiliated with the Filnemus rare disease healthcare network and the Euro-NMD (Newcastle) European reference network. Authors also belong to the research team "Genetics of Mitochondrial Disease" at the Institute for Research on Cancer and Aging (IRCAN).

Acknowledgments

We thank the ANR (Agence Nationale de la Recherche, ANR-16-CE16-0024-01), the AFM-Téléthon (Association Française contre les Myopathies, #20947), and the Fondation Maladies Rares for financial support.

Revision History

• 27 May 2021 (ha) Comprehensive update posted live
• 1 July 2015 (me) Review posted live
• 20 January 2015 (saem) Original submission

Published Guidelines / Consensus Statements

• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 2-9-23.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 2-9-23.

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