Mitochondrial Membrane Protein-Associated Neurodegeneration

Clinical characteristics.

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is characterized initially by gait changes followed by progressive spastic paresis, progressive dystonia (which may be limited to the hands and feet or more generalized), neuropsychiatric abnormalities (e.g., emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity), and cognitive decline. Additional early findings can include dysphagia, dysarthria, optic atrophy, axonal neuropathy, parkinsonism, and bowel/bladder incontinence. Survival is usually well into adulthood. End-stage disease is characterized by severe dementia, spasticity, dystonia, and parkinsonism.

Diagnosis/testing.

The diagnosis of MPAN is confirmed in individuals with biallelic pathogenic variants in C19orf12. (Although no non-molecular tests are able to reliably distinguish MPAN from other NBIA disorders, postmortem neuropathologic examination in individuals in whom molecular testing was not performed may help support the diagnosis of MPAN.)

Management.

Treatment of manifestations: Pharmacologic treatment of spasticity, dystonia, and parkinsonism; psychiatric treatment of significant neuropsychiatric symptoms; physical, occupational, speech, and other therapies as indicated. Nutritional supplements and gastric feeding as needed. Management of excessive secretions and aspiration risk with glycopyrrolate, transdermal scopolamine patch, and/or tracheostomy as indicated.

Surveillance: Routine follow up by a neurologist for medication management and interval assessment of ambulation, speech, and swallowing (often done every 3-6 months, but may be annual for patients who are more stable). Monitoring of patients receiving dopaminergic drugs for parkinsonism for adverse neuropsychiatric effects, and monitoring of patients receiving dopamine antagonist agents for psychiatric symptoms for the development or worsening of parkinsonism. Annual ophthalmologic examination is recommended.

Genetic counseling.

MPAN is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified. (Note: Possible autosomal dominant inheritance in one family has been reported.)

Clinical Diagnosis

While formal guidelines have not yet been developed to aid in the identification of mitochondrial membrane protein-associated neurodegeneration (MPAN), several of the predominant features of the disorder help distinguish it from other forms of neurodegeneration with brain iron accumulation (NBIA).

The diagnosis of MPAN is suspected in individuals with the following:

• Onset in childhood to early adulthood with slow progression and survival well into adulthood
• Cognitive decline progressing to severe dementia
• Prominent neuropsychiatric abnormalities including emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity
• Optic atrophy
• Dystonia, often of the hands and feet
• Muscle weakness
• Early spasticity sometimes followed by flaccid paresis
• Babinski sign
• Dysarthria
• Iron accumulation observed on brain MRI in both the globus pallidus and substantia nigra (Figure 1B). Serial MRI studies show that iron accumulation and brain atrophy progress with the disease course. To date, abnormal brain iron accumulation has been associated with all but two molecularly confirmed cases of MPAN (affected sisters) [Landouré et al 2013] (see Genetically Related Disorders). Since most affected individuals are identified following abnormal brain MRI studies, this strong correlation may reflect ascertainment bias.

Figure 1.

Imaging in MPAN A. Typical eye-of-the-tiger sign seen in PKAN

The diagnosis of MPAN is further supported by the following findings:

• Dysphagia
• Motor axonopathy with a pattern of distal denervation observed on electromyography and nerve conduction studies consistent with the clinical findings of distal to proximal loss of deep tendon reflexes.
• Parkinsonism (bradykinesia, rigidity, tremor, postural instability, and/or REM sleep behavior disorder)
• Incontinence of bowel and/or bladder
• On T₂-weighted brain MRI some individuals have hyperintense streaking of the medial medullary lamina between the globus pallidus interna and externa that could be mistaken for an eye-of-the-tiger sign (Figure 1C). Other less frequent MRI abnormalities include generalized cortical atrophy and cerebellar atrophy [Hogarth et al 2013, Schottmann et al 2014] and T₁-weighted hyperintensity in the caudate nucleus and putamen [Schulte et al 2013].

The diagnosis of MPAN is confirmed in individuals with biallelic pathogenic variants in C19orf12 (Table 1). (Note: Although no non-molecular tests are able to reliably distinguish MPAN from other NBIA disorders, postmortem neuropathologic examination (see Neuropathology) in individuals in whom molecular testing was not performed may help support the diagnosis of MPAN.)

One molecular genetic testing strategy is sequence analysis of C19orf12, the only gene in which pathogenic variants are known to cause MPAN.

Another molecular genetic testing strategy is use of a multigene panel that includes C19orf12 and other genes of interest (see Differential Diagnosis). 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.

Clinical Description

Onset of mitochondrial membrane protein-associated neurodegeneration (MPAN) typically occurs in childhood (3-16 years) to early adulthood (16-24 years) but has been reported as late as age 30 years. Among sibs the age of onset is similar.

The phenotypic spectrum of MPAN is likely to broaden as more cases are described. Fewer than 100 cases have been described to date.

Unlike in many other forms of neurodegeneration with brain iron accumulation (NBIA), the progression of MPAN is usually slow with survival well into adulthood. However, rare individuals with abrupt adult onset and rapid progression have been reported [Dogu et al 2013, Hogarth et al 2013].

Individuals with MPAN learn to walk and are usually mobile into early adulthood [Hartig et al 2011]. The most common presenting feature is impaired gait. Some present with vision impairment associated with optic atrophy, which is more common in childhood-onset than adult-onset MPAN and is strongly associated with homozygosity for a common deletion c.204_214del11 [Hartig et al 2011, Hogarth et al 2013].

Early gait changes are typically followed by the onset of progressive spastic paresis. The lower limbs are usually affected earlier and more significantly than the upper limbs. Reflexes are initially brisk, and the majority of affected individuals develop extensor plantar responses. Later in the disease course, lower motor neuron signs emerge, with loss of deep tendon reflexes from distal to proximal, variably accompanied by muscle atrophy. In three families, juvenile-onset mixed upper and lower motor neuron dysfunction mimicking amyotrophic lateral sclerosis was the presenting and salient feature [Deschauer et al 2012, Schottmann et al 2014].

Dystonia is also common and progressive. It may be limited to the hands and feet or more generalized. Dysarthria has been reported in most patients, and dysphagia in about half.

Parkinsonism also occurs in about half of individuals reported, with varying combinations of bradykinesia, rigidity, tremor, postural instability, and REM sleep behavior disorder. Parkinsonism is more common in adult-onset MPAN, particularly in those with rapid progression; however, it can develop late in the course of juvenile-onset MPAN.

Progressive cognitive decline is the norm in MPAN, in contrast to the common pantothenate kinase-associated neurodegeneration (PKAN) form of NBIA.

Neuropsychiatric changes are also frequent and varied; they include depression, anxiety, emotional lability, compulsions, hallucinations, perseveration, impulsivity, inattention, and hyperactivity.

While incontinence has been noted late in the course of other forms of NBIA, some individuals with MPAN develop this earlier in disease while they may still be ambulatory with little cognitive decline [Hogarth et al 2013].

The end stages of MPAN are characterized by severe dementia, spasticity, dystonia, and parkinsonism. Affected individuals are no longer ambulatory; communication is limited due to dysarthria and cognitive decline. Weight loss and bowel and/or bladder incontinence are common. Persons with advanced disease may have stereotypic hand or head movements with alterations in consciousness that do not appear to be related to seizures. Death typically occurs secondary to complications such as aspiration pneumonia.

Genotype-Phenotype Correlations

Individuals homozygous for the common deletion c.204_214del11, reported originally in a Polish cohort, have childhood-onset disease with optic atrophy [Hartig et al 2011, Hogarth et al 2013].

The pathogenic variant c.32C>T is associated with later disease onset (mean age of 25 years for persons homozygous for c.32C>T) compared to a mean age of ten years for all published cases [Hartig et al 2013].

Prevalence

MPAN is a newly recognized form of NBIA with a prevalence roughly estimated at less than one in 1,000,000. Fewer than 100 cases with molecular confirmation have been described to date.

As the awareness of MPAN increases and molecular testing is used more frequently, a better estimation may be made.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with mitochondrial membrane protein-associated neurodegeneration (MPAN), the following evaluations are recommended:

• Complete neurologic examination, including evaluation of ambulation, speech, and swallowing
• Ophthalmologic examination to assess for optic atrophy
• Assessment by specialists in physical, occupational, and/or speech therapy
• Brain MRI (T₂-weighted at a minimum) if one has not been obtained within the past two years
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The following are indicated:

• Pharmacologic treatment of dystonia and spasticity, including consideration of oral baclofen, trihexyphenidyl, intramuscular botulinum toxin, and a trial of intrathecal baclofen if indicated
• Pharmacologic treatment of parkinsonism (response to levodopa has been variable in this population)
• Treatment by a psychiatrist for those with significant neuropsychiatric symptoms
• Physical, occupational, speech, and other therapies as indicated
• Use of a liquid nutritional supplement to help maintain weight as needed
• A gastric feeding tube to help minimize weight loss (which becomes more frequent with disease progression) and to reduce the risk of aspiration pneumonia
• Glycopyrrolate or transdermal scopolamine patch to reduce the volume of secretions in those with excessive drooling or difficulty controlling secretions
• Tracheostomy as indicated for difficulty managing secretions
• Over-the-counter fiber supplements and/or stool softeners to treat constipation, which is likely caused by a combination of immobility, diet, and medications

Surveillance

Patients are typically followed most closely by a neurologist for medication management and for interval assessment of ambulation, speech, and swallowing. This is often done every three to six months, but may be annual for patients who are more stable.

Patients receiving dopaminergic drugs (for parkinsonism) are monitored for adverse neuropsychiatric effects; conversely, patients receiving typical or atypical dopamine antagonist agents (for psychiatric features) are monitored for the development or worsening of parkinsonism.

Annual ophthalmologic examination is recommended.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Deep brain stimulation (DBS) has not been specifically studied in MPAN, even in case reports. DBS has become a common treatment for primary dystonia and is being used more frequently to attempt to treat the secondary dystonia in PKAN with some success. It is likely that the use of DBS in MPAN will eventually be reported.

Iron chelation using deferiprone is currently under investigation in PKAN (see ClinicalTrials.gov). A small Phase II pilot trial in PKAN showed statistically significant reduction of brain iron by MRI evaluation; however, no change in clinical status was observed [Zorzi et al 2011]. The current double-blind, placebo-controlled trial in PKAN may inform whether deferiprone treatment should be considered for MPAN.

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.