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 [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.