Chchd10-Related Disorders

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2021-01-18
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Summary

Clinical characteristics.

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

  • Mitochondrial myopathy (may also be early-onset): weakness, amyotrophy, exercise intolerance
  • Amyotrophic lateral sclerosis (ALS): progressive degeneration of upper motor neurons (UMNs) and lower motor neurons (LMNs)
  • Frontotemporal dementia (FTD): slowly progressive behavioral changes, language disturbances, cognitive decline, extrapyramidal signs
  • Late-onset spinal motor neuronopathy (SMAJ): weakness, cramps, and/or fasciculations; areflexia
  • 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 CHCHD10-related disorders 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. Prenatal testing for pregnancies at increased risk is possible.

Diagnosis

Suggestive Findings

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

Note: Cerebellar ataxia may be present in combination with mitochondrial myopathy, ALS, and/or FTD.

Clinical Findings

Mitochondrial myopathy

  • Signs of muscle weakness (proximal, axial, and/or facial, including ptosis), amyotrophy, or symptoms that suggest respiratory chain dysfunction, such as exercise intolerance

Amyotrophic lateral sclerosis (ALS)

  • Characteristic signs and symptoms of progressive degeneration of upper motor neurons (UMNs) and lower motor neurons (LMNs)
  • UMN manifestations include stiffness, spasticity, hyperreflexia, Babinski sign, and pseudobulbar palsy (dysphagia and dysarthria)
  • LMN manifestations include weakness accompanied by muscle atrophy, fasciculations, areflexia, and cramping

Note: Most individuals with CHCHD10-related ALS meet El Escorial criteria for ALS [Brooks et al 2000] and have both UMN and LMN involvement. (See also the Amyotrophic Lateral Sclerosis Overview.)

Frontotemporal dementia (FTD)

  • Slowly progressive behavioral changes (disinhibition, loss of initiative, loss of interest in environment, psychiatric symptoms) [Bird et al 1999, Mioshi et al 2010]
  • Language disturbances (word-finding difficulties and semantic paraphasias, perseveration, and echolalia, mutism) [Gorno-Tempini et al 2011]
  • Cognitive decline (executive dysfunctions, attention disorders, and abstract reasoning inability)
  • Extrapyramidal signs (rigidity, bradykinesia)

Late-onset spinal motor neuronopathy (SMN) or spinal muscular atrophy, Jokela type (SMAJ)

  • LMN manifestations including: weakness, cramps, and/or fasciculations that are more proximal than distal; areflexia

Cerebellar ataxia

  • Gait ataxia
  • Kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements)
  • Dysarthria
  • Dysphagia
  • Nystagmus
  • Cerebellar oculomotor disorder

Supportive Laboratory Findings

Although none of the following laboratory findings is specific, all could be considered supportive findings.

Neuroimaging

  • Frontal and/or temporal atrophy on brain CT or MRI [Foster et al 1997, van Swieten et al 1999]
  • Decrease of cerebral perfusion anteriorly (single-photon emission computed tomography [SPECT])
  • Frontotemporal hypometabolism (positron emission tomography with 18F-fluorodeoxyglucose [FDG-PET]) [Foster et al 2007]
  • Reduced striatal uptake of 18F-fluoro-L-dopa [Wszolek et al 1992]

Muscle biopsy findings that support the diagnosis of a mitochondrial myopathy are ragged-red and/or COX negative fibers with or without multiple mtDNA deletions. Note that a muscle biopsy is not required for diagnosis of a CHCHD10-related disorder.

Electromyography and nerve conduction studies (EMG/NCS) demonstrate widespread denervation due to LMN loss in the setting of relatively preserved sensory responses [Gitcho et al 2008, Kühnlein et al 2008].

Serum CK concentration is normal or high.

Establishing the Diagnosis

The diagnosis of a CHCHD10-related disorder is established when a heterozygous pathogenic variant is detected in CHCHD10 (Table 1) in a proband with one or more of the above clinical findings.

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

  • Single-gene testing. Sequence analysis of CHCHD10 is most appropriate in individuals whose family history suggests a CHCHD10-related disorder and in individuals in whom other more common molecular causes of ALS / FTD-ALS / MND (motor neuron disease) have already been ruled out.To date no CHCHD10 deletions/duplications have been reported.
    Targeted analysis for the p.Gly66Val pathogenic variant can be performed first in individuals of Finnish ancestry with late-onset spinal motor neuronopathy (SMN) (SMAJ) [Penttilä et al 2015].
  • A multigene panel that includes CHCHD10 and other genes of interest (see Differential Diagnosis) can also be considered as the initial test. 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; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (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.
  • More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes CHCHD10) fails to confirm a diagnosis in an individual with features of a CHCHD10-related disorder. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in CHCHD10-related Disorders

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
CHCHD10Sequence analysis 2All pathogenic variants reported to date 3
Gene-targeted deletion/duplication analysis 4None reported to date
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

Fewer than ten missense variants have been associated with a CHCHD10-related disorder. A founder variant (p.Gly66Val) was identified in 55 individuals from 17 Finnish families [Penttilä et al 2015]. The p.Arg15Leu pathogenic variant was identified in six of 213 families with ALS [Johnson et al 2014, Müller et al 2014, Kurzwelly et al 2015]. Additional missense variants were identified in families [Bannwarth et al 2014, Chaussenot et al 2014, Ajroud-Driss et al 2015, Dobson-Stone et al 2015, Zhang et al 2015] and simplex cases (a single occurrence in a family) [Chaussenot et al 2014, Ronchi et al 2015, Zhang et al 2015].

4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Clinical Characteristics

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, and late-onset spinal motor neuronopathy. Cerebellar ataxia may also be found in combination with these disorders, but not as the sole neurologic manifestation.

CHCHD10 pathogenic variants were originally identified in: (1) a large family with late-onset frontotemporal dementia (FTD), motor neuron disease (MND), cerebellar ataxia, and mitochondrial myopathy with mtDNA deletions [Bannwarth et al 2014] and (2) a large family with early-onset mitochondrial myopathy without mtDNA deletions [Ajroud-Driss et al 2015].

CHCHD10 pathogenic variants have also been described in individuals with frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) and familial and sporadic pure ALS [Chaussenot et al 2014, Johnson et al 2014, Müller et al 2014, Kurzwelly et al 2015, Ronchi et al 2015, Zhang et al 2015].

More recently, a CHCHD10 founder variant has been identified in 17 Finnish families with late-onset spinal motor neuronopathy (SMAJ) [Penttilä et al 2015].

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 late-onset spinal motor neuronopathy (SMAJ) caused by the p.Gly66Val pathogenic variant) is largely unknown.

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 MND, FTD, and cerebellar ataxia [Bannwarth et al 2014].

Amyotrophic lateral sclerosis (ALS). The manifestations of ALS in CHCHD10-related disorders appear to overlap significantly with idiopathic and SOD1-related ALS (see ALS Overview), including gender ratio, age of onset, symptom distribution, and severity of disease. Mean age of onset is 53 years (age range 25-75 years).

Although presentations of ALS of various etiologies may overlap, in CHCHD10-related ALS phenotypes the upper limbs seem to be more frequently involved at the onset and in CHCHD10-related FTD-ALS bulbar involvement is more predominant.

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.

Intra- and interfamilial variability is observed even with the same CHCHD10 pathogenic variant. Mean disease duration prior to death is 8.6 years (range 2-17 years).

Note: CHCHD10-related ALS is clinically indistinguishable from ALS of other causes. However, based on published data, CHCHD10-related ALS may include upper-limb onset, flail-arm syndrome, and bulbar signs [Müller et al 2014, Bannwarth et al 2015, Kurzwelly et al 2015, Ronchi et al 2015]. Nevertheless, even within a family, clinical variability is considerable, especially regarding age of onset and longevity.

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, language disturbance, and/or extrapyramidal signs. In individuals with CHCHD10-related FTD, symptoms started between ages 50 and 67 years. Disease duration was usually between four and 27 years. The disease progresses over a few years into profound dementia with mutism.

  • 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].
  • Psychiatric manifestations. Persecutory delusions and visual or auditory hallucinations occur rarely in FTD and were not reported in individuals with mutation of CHCHD10.
  • 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. The extrapyramidal signs are unresponsive or only partially responsive to L-dopa treatment.

Spinal motor neuronopathy in CHCHD10-related disorders (SMAJ) is characterized by late onset. Affected individuals develop cramps and fasciculations, slowly progressive and predominantly lower-limb weakness, and diminished or absent deep tendon reflexes; respiratory symptoms are absent. 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].

Cerebellar ataxia in CHCHD10-related disorders is characterized by ataxia, dysarthria, and eventual deterioration of bulbar functions. Onset is in the sixth decade. Affected individuals have difficulties in gait and slurred speech. They may first notice problems of balance 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.

As the disease progresses saccadic velocity slows and up-gaze palsy develops. Nystagmus often disappears with evolving saccadic abnormalities.

As the ataxia worsens, other cerebellar signs such as dysmetria, dysdiadochokinesia, and hypotonia become apparent.

Neuropathology. To date no study of brain pathology has been performed in an individual with a CHCHD10-related disorder.

Genotype-Phenotype Correlations

No obvious genotype-phenotype correlation exists.

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.

The same CHCHD10 pathogenic variant can lead to different phenotypes; for example, individuals with the p.Ser59Leu pathogenic variant had different findings including ataxia and/or FTD and/or ALS; the only element common to all affected individuals from the large French family was the laboratory finding of a mitochondrial myopathy with numerous ragged-red and COX-negative fibers associated with multiple mtDNA deletions [Bannwarth et al 2014]. No muscle biopsy was available from the affected individual with the same pathogenic variant reported by Chaussenot et al [2014].

However, it should be noted that:

  • The p.Arg15Leu pathogenic variant appears to predominate in familial pure ALS [Johnson et al 2014, Müller et al 2014, Kurzwelly et al 2015].
  • The p.Arg15Leu and p.Pro80Leu variants may be associated with fly-arm or predominant upper-limb involvement [Müller et al 2014, Kurzwelly et al 2015, Ronchi et al 2015].
  • The p.Gly66Val pathogenic variant was identified as a founder variant in 17 Finnish families with SMAJ [Penttilä et al 2015]. Bulbar symptoms, mitochondrial myopathy, and cognitive dysfunction were exceptional findings in SMAJ even after decades of follow up, in contrast to individuals with the p.Ser59Leu pathogenic variant, for whom these were the most prominent clinical features [Bannwarth et al 2014, Chaussenot et al 2014].

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.

Complete penetrance was described in all families with a CHCHD10 pathogenic variant [Bannwarth et al 2014, Ajroud-Driss et al 2015, Kurzwelly et al 2015, Penttilä et al 2015] except two families with ALS and the p.Arg15Leu variant [Müller et al 2014] and one with the p.Pro34Ser variant [Dobson-Stone et al 2015]. More reports will be needed before the penetrance can be more accurately established.

Prevalence

The prevalence of CHCHD10-related disorders is not known at present. However, based on the first published series, prevalence of CHCHD10-related disorders is estimated at 1.4%-3.5% in individuals of European ancestry with ALS or the FTD-ALS spectrum [Dobson-Stone et al 2015].

Mutation of CHCHD10 appears to rank immediately following mutation of C9ORF72 and SOD1 as a cause of sporadic ALS [Renton et al 2011].

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

Differential Diagnosis

Mitochondrial myopathy. For a detailed discussion and the differential diagnosis of mitochondrial myopathy, see Mitochondrial Disorders Overview.

Sporadic and familial ALS. For a detailed discussion of these disorders and the differential diagnosis of ALS, see Amyotrophic Lateral Sclerosis Overview.

Familial ALS (FALS) (i.e., presence of at least two affected family members)

  • Because approximately 20% of FALS is caused by mutation of SOD1 and approximately 30% by mutation of C9ORF72, a tiered approach to testing a proband with autosomal dominant FALS should begin with C9ORF72 and SOD1 sequencing.
  • If neither a C9ORF72 nor a SOD1 pathogenic variant is identified, sequencing of CHCHD10 should be performed. Based on published data available to date, variants in CHCHD10 appear to be the third most common cause of FALS [Johnson et al 2014, Müller et al 2014, Kurzwelly et al 2015, Zhang et al 2015].
  • Although in some instances testing for other rare genetic causes of FALS can be considered, these disorders have a distinctive clinical presentation or autosomal recessive inheritance pattern (see Amyotrophic Lateral Sclerosis Overview).

Sporadic ALS (SALS) (i.e., single occurrence in a family). Sequencing of CHCHD10 in SALS can be performed.

  • Ronchi et al [2015] also identified the CHCHD10 variants p.Pro34Ser (2 patients) and p.Pro80Leu (1 patient) in Italians with sporadic ALS/FTD-ALS corresponding to 1.4% of Italians with a diagnosis of probable or definite motor neuron disease.
  • In the data sets of Zhang et al [2015] the estimated mutation frequency is 1.2% for sporadic ALS.

Sporadic or familial FTD-ALS (i.e., presence of at least two affected family members)

  • Because FTD/ALS is mainly caused by mutation of C9ORF72, MAPT, FUS1, GRN, TARDBP, and VCP, a tiered approach to testing a proband with autosomal dominant familial FTD-ALS should begin with sequencing of these genes.
  • If no pathogenic variant is identified in C9ORF72, MAPT, FUS1, GRN, TARDBP, or VCP, sequencing of CHCHD10 should then be performed.

CHCHD10-associated ALS must be differentiated from mimics of ALS. Detailed clinical evaluation (as outlined above) usually allows the exclusion of other disorders. The rate of misdiagnosis in ALS is highest in individuals presenting with purely lower motor neuron findings [Traynor et al 2000].

Disorders of any cause that mimic ALS are numerous and include:

  • Multifocal motor neuropathy
  • Cervical spondylosis
  • Adult-onset spinal muscular atrophy (SMA)
  • Kennedy disease (X-linked spinobulbar muscular atrophy [SBMA])
  • Acquired and hereditary motor neuropathies (see Charcot-Marie-Tooth Hereditary Neuropathy Overview)
  • Late-onset GM2 gangliosidosis (see Hexosaminidase A Deficiency)
  • Adult polyglucosan body disease

See Table 2 for a list of other genes associated with FALS.

Table 2.

Other Genes Associated with FALS

GeneSelected GeneReviewProteinSelected OMIM
ANGALS OverviewAngiogenin611895
DCTN1ALS OverviewDynactin105400
FUS/TLSALS OverviewFused in sarcoma/translated in liposarcoma608030
SETXALS OverviewSenataxin602433
SOD1ALS OverviewSuperoxide dismutase [Cu-Zn]105400
TARDBPTARDBP-Related ALSTAR DNA-binding protein 43612069
VAPBALS OverviewVesicle-associated membrane protein-associated protein B/C608627
VCPInclusion Body Myopathy w/Paget Disease of Bone and/or FTDTransitional endoplasmic reticulum ATPase613954

Pathogenic variants in many of these genes have also been identified in small numbers of simplex cases of ALS (i.e., a single occurrence of ALS in a family).

FTD-ALS. Structural imaging may show focal atrophy and may exclude other causes of dementia (e.g., frontal meningioma, chronic subdural hematoma).

The disorders of any cause that mimic FTD include:

  • Alzheimer disease when individuals present with mild behavioral changes, prominent memory disturbance and loss of initiative, or word-finding problems in the absence of evident frontotemporal atrophy on neuroimaging.
  • Familial Parkinson disease when parkinsonism is present (see Parkinson Disease Overview). Other familial neurologic diseases associated with dementia or parkinsonian features including Huntington disease, dementia with Lewy bodies, and prion diseases also need to be considered.

Non-genetic acquired causes of dementia should always be considered.

About 25% of persons with FTD have a positive family history and demonstrate an autosomal dominant pattern of inheritance.

See Table 3 for a list of other genes associated with FTD-ALS.

Table 3.

Other Genes Associated with FTD-ALS

GeneSelected GeneReviewProteinSelected OMIM
C9orf72C9orf72-Related ALS & FTDUncharacterized protein C9orf72105550
CHMP2BFTD, Chromosome 3-LinkedCharged multivesicular body protein 2b600795
GRN (PGRN)GRN-Related FTDGranulins607485
MAPTMicrotubule-associated protein tau600274
TARDBPTARDBP-Related ALSTAR DNA-binding protein 43612069
VCPInclusion Body Myopathy w/Paget Disease of Bone and/or FTDValosin-containing protein167320

Pathogenic variants in many of these genes have also been identified in small numbers of simplex cases of ALS (i.e., a single occurrence in a family).

ALS = amyotrophic lateral sclerosis; FTD = frontotemporal dementia

Cerebellar ataxia. For a detailed discussion and the differential diagnosis of inherited ataxias myopathy, see Hereditary Ataxia Overview.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with a CHCHD10-related disorder, the following evaluations are recommended:

  • A structured general medical history and family history
  • Physical examination and neurologic examination
  • EMG/NCS to document the regions of involvement and indicate lower motor neuron and/or myopathic involvement
  • Evaluation of the extent and profile of cognitive disturbance by neuropsychological examination
  • Neuroimaging with MRI if not done at time of initial diagnosis.
  • Pulmonary function testing to detect and stage respiratory involvement
  • Speech and swallowing evaluation if dysarthria and/or dysphagia are present to direct care to minimize risk of aspiration and to initiate augmentative communication strategies for possible loss of verbal communication
  • Audiologic examination, including auditory brain stem responses (ABRs) and evoked otoacoustic emissions
  • Physical and occupational therapy evaluation to determine the adaptive devices needed to maximize function
  • Nutritional evaluation
  • Screening to detect depression and assess need for psychosocial support
  • Clinical genetics consultation

Treatment of Manifestations

General

  • Adequate nutrition and weight maintenance are essential. Percutaneous gastrostomy is often appropriate to maintain adequate caloric intake in persons with significant bulbar involvement.
  • Joint contractures can occur, are often painful, and can interfere with caregiving. Appropriate bracing and stretching can minimize contractures.

Mitochondrial myopathy

  • Assistance with ambulation and posture
  • Surgical correction of ptosis as needed

Amyotrophic lateral sclerosis (ALS). The management of CHCHD10-related ALS is identical to that of ALS due to other causes, and is outlined in the American Academy of Neurology practice parameter on this topic [Miller et al 1999].

  • Spasticity can be treated with a spasmolytic such as baclofen or a benzodiazepine.
  • Pseudobulbar affect can be treated with a tricyclic antidepressant or combination of quinidine and dextromethorphan.
  • Sialorrhea is often managed with anticholinergic medications (tricyclic antidepressants, scopolamine, atropine drops) or botulinum toxin injection of the salivary glands.
  • Antidepressants are often required to treat concurrent depression.
  • Riluzole is the only FDA-approved treatment for any type of ALS. Although there are no efficacy data specifically for CHCHD10-related ALS, strong consideration should be given to its use.

Frontotemporal dementia (FTD). Treatment follows routine practices.

  • Sedative or antipsychotic drugs help to reduce extreme restlessness, roaming behavior, delusions, and hallucinations.
  • The extrapyramidal signs are usually unresponsive or only partially responsive to L-dopa treatment.
  • Behavioral changes and the loss of insight and judgment in individuals with FTD often present a considerable burden for partners or other caregivers. Information about the disease and psychological support for partners or other caregivers is essential.

Spinal motor neuronopathy. The management of SMAJ is identical to that of adult-onset SMA due to other causes.

Surveillance

The following regular evaluations are indicated to detect manifestations that can occur with time:

  • Neurologic deficits. Neurologic examination including assessment of memory, personality changes
  • Psychiatric abnormalities. Assessment for signs including depression and suicidal ideation
  • Impaired respiratory function. Monitoring of forced vital capacity (FEV) and other aspects of respiratory function performed at clinic visits to determine the appropriate time to offer noninvasive ventilation
  • Sensorineural hearing loss. Audiologic examination including speech discrimination testing

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

A clinical trial with the selective serotonin reuptake inhibitor (SSRI) paroxetine showed an increase in cognitive impairment in patients with FTD treated with this drug [Deakin et al 2004]. Conversely, a previous study with another SSRI, trazodone, showed a favorable effect on behavioral disturbances and agitation without cognitive decline [Lebert et al 2004]. Further studies are needed to clarify this issue.

Several trials with memantine are underway in patients with FTD, as well as a trial with oxytocin and its effect on social cognition.

Although no current clinical trials are specifically designed to target CHCHD10-related disorders, many are addressed in the broader category of ALS or FTD.

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.