MPAN is caused by mutations in C19orf12 leading to NBIA and prominent, widespread Lewy body pathology. The clinical phenotype, while sharing features with other forms of NBIA, is recognizable and distinctive (). This newly recognized autosomal recessive subtype joins PKAN and PLAN as one of the major forms of NBIA, accounting for approximately 5% of cases. In our registry of patients ascertained for the presence of high basal ganglia iron by MRI or postmortem examination, the distribution of NBIA subtypes is depicted in figure e-1 (MPAN frequency is based on the number of mutation-positive unrelated families in our cohort).
Distinguishing features of the most common neurodegeneration with brain iron accumulation subtypes
Our cohort offers an expanded view of the MPAN phenotype compared to the more ethnically homogenous population reported previously.2
The characteristic clinical features of MPAN across all age groups include cognitive decline progressing to dementia, prominent neuropsychiatric abnormalities, and a motor neuronopathy, with early upper motor neuron findings followed later by signs of lower motor neuron dysfunction and spheroid pathology. In juvenile-onset MPAN, these findings are joined by early optic atrophy, and in adult-onset disease by parkinsonism. Features that are variably present include dysarthria, dysphagia, dystonia-parkinsonism, bowel and bladder dysfunction, stereotypic hand and head movements, and proprioceptive sensory abnormalities dissociated from vibratory loss. Universally present in our cohort ascertained for this feature was a distinctive pattern of brain iron accumulation, characterized by T2/gradient echo hypointensities in the substantia nigra and globus pallidus, often with unique T2-hyperintense streaking between the hypointense internal globus pallidus and external globus pallidus. Like other forms of NBIA, MPAN spans a phenotypic spectrum that is likely to continue to broaden as more cases are described. Phenotypes outside of this recognized spectrum but associated with mutations in C19orf12
are likely to be discovered as more individuals with undiagnosed neurologic and neuropsychiatric disorders undergo whole genome sequencing.
A variety of mutations account for disease in our ethnically diverse cohort. While a substantial number harbor an Eastern European founder mutation, most patients have private mutations. Nonsense, frameshift, and missense mutations were distributed throughout the small coding region of C19orf12
. Based on our results in 3 patients in whom we found only a single heterozygous mutant allele, occult deleterious mutations are likely to be present in noncoding sequence. Therefore, we recommend that intronic and regulatory sequences be screened in order to increase detection of disease-associated mutations. Multiplex ligation-dependent probe amplification may increase detection rates; however, we found no evidence for large duplications or deletions in our cohort. Additionally, we observed the co-occurrence of sequence variations c.205G>A and c.424A>G in 4 families (table e-1), 3 of which also had a third variation predicted to be pathogenic. Based on prediction algorithms described in Methods and the presence of the third variant in 3 of the families, we postulated that c.424A>G is an innocuous SNP that travels in cis with the pathogenic c.205G>A mutation. Clinical testing for MPAN is now available (www.genetests.org
Though many lines of evidence support an autosomal recessive pattern in most cases of MPAN, one of our single-mutation patients (437) had a family history consistent with dominant inheritance. His father died at age 47 following a long course of progressive dementia with parkinsonism. Postmortem examination of the father's brain demonstrated neuropathologic changes nearly identical to those reported herein from an unrelated patient, including widespread abundant Lewy bodies, and both axonal spheroids and increased iron in globus pallidus and substantia nigra. Interestingly, the single unique frameshift mutation identified in this family leads to a series of 32 amino acid substitutions followed by a premature stop codon only 2 amino acids before the normal termination. The aberrant protein product is likely to escape nonsense-mediated mRNA decay and may exert a dominant negative effect on normal protein. Further studies in this family are underway to examine this possibility.
Lewy bodies are common in nearly all forms of NBIA, including MPAN, with PKAN being the only major form not associated with α-synuclein pathology. They appear much more abundant in non-PKAN hereditary NBIA, however, than in sporadic α-synucleinopathies, especially in neocortical areas in which Lewy bodies are typically relatively sparse in sporadic α-synucleinopathies such as dementia associated with PD, over which they were increased approximately 40× in MPAN (vs 6× in PLAN). Lewy bodies in sporadic illness are hypothesized to arise through increased α-synuclein expression or decreased degradation through the ubiquitin-proteasome and autophagy-lysosomal pathways.10
In MPAN, the markedly increased burden of Lewy bodies throughout the neocortex, deep gray matter, and midbrain suggest that alterations in the protein encoded by C19orf12
have profound effects on these pathways. Although amyloid-β abnormalities strongly drive α-synuclein accumulation in the cortex in sporadic neurodegenerative disease, there was no evidence in MPAN brain for amyloid-β by immunohistochemistry. There is a large body of literature that implicates mitochondrial dysfunction in the pathogenesis of PD, and the major toxicologic models of PD (MPTP, rotenone, and paraquat) uniformly affect complex I of the respiratory chain. However, the precise target of these toxins remains unknown. Given the massive α-synucleinopathy observed in MPAN, we speculate that C19orf12
may be a key susceptibility factor in PD and other α-synucleinopathies, as well as in models of these diseases.
Although little is known about the function of the protein encoded by C19orf12, its profile fits with proteins that are defective in other forms of NBIA. Mitochondrial membrane association and coregulation with proteins of fatty acid biogenesis and branched chain amino acid degradation expression profiles suggest similarities to other NBIA proteins, including PANK2, PLA2G6, and FA2H. Insight into protein function and disease pathogenesis will be accelerated by the creation of animal models of disease, which are currently in development.