Mitochondrial Protein-associated Neurodegeneration Research Articles

Secondary tauopathy in a genetic synucleinopathy, mitochondrial protein–associated neurodegeneration (MPAN)

AbstractBackgroundTauopathy and α‐synucleinopathy often occur together in human brain diseases but most commonly in the context of β‐amyloidosis. Tauopathy induced by α‐synucleinopathy in the absence of β‐amyloid has been demonstrated in vitro and in cultured cells but compelling examples of this in human disease rarely occur, most commonly in familial Parkinson's disease due to mutations in the α‐synuclein gene. Mitochondrial protein‐associated neurodegeneration (MPAN) due to mutations in C19orf12 produces neurodegeneration with brain iron accumulation as well as widespread α‐synucleinopathy. We report here on the findings and significance of associated tauopathy in MPAN.MethodFour patients with genetically confirmed MPAN were referred for brain autopsy and a complete histologic and immunohistochemical evaluation was undertaken for lesions and proteinopathies of common neurodegenerative diseases as well as the specific reported lesions of MPAN.ResultAll patients had hallmark pathologic features of MPAN including atrophy, gliosis, and iron accumulation involving the globus pallidus as well as abundant α‐synucleinopathy manifest as Lewy bodies and neurites thoughout the brain. Tauopathy was present in each case with neurofibrillary tangles distributed in Braak stages I to V with pretangles and more widely distributed tau‐positive dystrophic neurites. The distribution and regional burden of tauopathy was less than that of α‐synucleinopathy in each case. β‐amyloid or TDP‐43 abnormalities were not identified in any case.ConclusionThe lesional burden and distribution in MPAN are consistent with a pathogenetic model in which dysmetabolism of α‐synuclein is sufficient, in the absence of other common neurodegenerative pathologies, to induce tauopathy. Study of rare familial diseases such as MPAN may enhance our understanding of the pathogenesis of more common idiopathic neurodegenerative diseases.

From the Hallervorden-Spatz eponym to the molecular terminology

A combination of Niemann-Pick- and Hallervorden-Spatz diseases led to the death of a 17-year-old boy in 1994. Genetic counseling necessitated further investigations in 2017. Meanwhile, the nomenclature of Hallervorden-Spatz disease has been abandoned. The author analyze the reasons for this change. Professional activities of Hallervorden and Spatz during and after the Nazi euthanasia program are presented. Also, the scientific efforts that led to the discovery of the genetic background of the disease and ultimately to its new name are highlighted. In nazi Germany, a large number of mentally disabled were killed. The majority of pediatric-brains were transferred to the "Kaiser Wilhelm Institut für Hirnforschung", led by Hugo Spatz, and was included in the "Hallervorden collection". Investigations exploring the connections between eponyms and nazi-activites started in the mid-1980s. This process was accelerated by the discovery of genetic alterations underlying disease entities, including neurodegeneration with brain iron accumulation (NBIA). NBIA has several subtypes, with the first being the disease described by Hallervorden and Spatz, and recently renamed to pantothenate kinase-associated neurodegeneration (PKAN). The case examined by the authors belongs to the third subtype, to the mitochondrial protein-associated neurodegeneration (MPAN). The works of the two noted neuropathologists strongly conflict with current ethical principles of human research studies. The buried "Hallervorden collection" in the Munich Waldfriedhof cemetery, and the memorial column erected there will remain a sad reminder of a time when a political system profoundly distorted the judgement of even academic physicians. Orv Hetil. 2017; 158(43): 1723-1727.

P79 – 2622: Juvenile-onset mitochondrial protein associated neurodegeneration – Case report

Introduction Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of diseases presenting with a progressive extrapyramidal syndrome and excessive iron deposition in the brain. Mutations in the C19orf12 gene were recently (2009) described as cause of NBIA (called mitochondrial membrane protein-associated neurodegeneration, MPAN). Objective We report a Turkish child diagnosed as MPAN with new mutation. Case report A previously healthy 14-year-old girl presented with progressive slowing of speech and movements, and also frequent drop attacks. Her past history and family history were unremarkable. First neurological examination revealed: hypomimia, dysarthria, echolalia, incoordination and propulsive gait. The initial brain magnetic resonance imaging (MRI) on admission was normal. Because of progressive neurologic detonation a repeat brain MRI was done after 3 years, on T2-weighted images showed low signal intensity in the globus pallidus and substantia nigra bilaterally. Because of clinical and radiological suggestion of iron deposition, the molecular analyses was done and revealed a new homozygous mutation in C19orf12 gene: p.A56LFs*6 (c.166delG) allowing the diagnosis of MPAN. In our case, lack of peripheral neuropathy, cognitive decline and neuropsychiatric symptoms and also normal EMG findings are unusual when compared to the typical course of the MPAN. This features may be related age or clinical outcome of new mutation. As presented case, initial brain MRI findings may be normal, if there is clinical suspicion of NBIA repeated brain MRI may be necessary. To the best of our knowledge, this is the first reported Turkish child who was diagnosed as MPAN. Conclusion MPAN should be considered as a differential diagnosis in patients with juvenile onset speech and gait disturbances, dystonia, parkinsonism and pyramidal signs. Patients have to be examined carefully to detect extra-motor symptoms such as neuropsychological abnormalities or optic neuropathy. Brain MRI should be evaluated for signs of iron accumulation.

OP10 – 2707: Childhood-onset ataxic gait solved by muscle biopsy

Objective The differential diagnosis of childhood-onset ataxia may be challenging, especially in the absence of brain MRI or lab abnormalities. We present a case where the findings of intra-axonal spheroids on muscle biopsy led to the diagnosis of atypical neuraxonal dystrophy (NAD) due to a compound heterozygous mutation in PLA2G6. Methods and results The proband was referred for frequent falls at age 4 years. Acquisition of early developmental milestones was normal. Concerns were first expressed at age 3 years, when she developed an unsteady gait. On examination eye movements were slightly saccadic, gait ataxic, balance poor. She had mild proximal muscle weakness with positive sign of Gowers. Deep tendon reflexes were present. She was at times introverted and sometimes overfamiliar. Formal evaluation of development showed normal intelligence, normal speech and language development except for intermittent whispering, and confirmed poor coordination and balance. Visuo-spatial skills were normal. Brain MRI was normal and remained so after 3 years. EMG and nerve conduction studies, fundoscopy, lactate, alpha-foetoprotein and urinary catecholamines were normal. Friedreich ataxia and Pompe disease were excluded. Further concern about a possible myopathy led to muscle biopsy. Histological examination showed a predominance of type1 fibers. Extensive immunohistochemical testing was normal. Electron microscopy revealed intra-axonal spheroids in the peri- and endomysial myelinated nerve bundles as well as in the motor endplates. Neuroaxonal spheroids are present in >80% of cases with PLA2G6-associated neurodegeneration (PLAN) and is rarely seen in mitochondrial protein associated neurodegeneration (MPAN). Mutation analysis of PLA2G6 showed the compound heterozygous presence of the c.1021G>A (p.Ala341Thr) and c.2036G>T (p.Gly679Val) mutations in the patient, while both parents were heterozygous carriers, confirming the diagnosis of atypical NAD. Conclusion This report highlights that childhood-onset gait ataxia with subtle behavioral and/or expressive speech abnormalities may be the presenting features of atypical NAD. The differential diagnosis of childhood-onset ataxia may be challenging, especially in the absence of brain MRI or lab abnormalities. We present a case where the findings of intra-axonal spheroids on muscle biopsy led to the diagnosis of atypical neuraxonal dystrophy (NAD) due to a compound heterozygous mutation in PLA2G6. The proband was referred for frequent falls at age 4 years. Acquisition of early developmental milestones was normal. Concerns were first expressed at age 3 years, when she developed an unsteady gait. On examination eye movements were slightly saccadic, gait ataxic, balance poor. She had mild proximal muscle weakness with positive sign of Gowers. Deep tendon reflexes were present. She was at times introverted and sometimes overfamiliar. Formal evaluation of development showed normal intelligence, normal speech and language development except for intermittent whispering, and confirmed poor coordination and balance. Visuo-spatial skills were normal. Brain MRI was normal and remained so after 3 years. EMG and nerve conduction studies, fundoscopy, lactate, alpha-foetoprotein and urinary catecholamines were normal. Friedreich ataxia and Pompe disease were excluded. Further concern about a possible myopathy led to muscle biopsy. Histological examination showed a predominance of type1 fibers. Extensive immunohistochemical testing was normal. Electron microscopy revealed intra-axonal spheroids in the peri- and endomysial myelinated nerve bundles as well as in the motor endplates. Neuroaxonal spheroids are present in >80% of cases with PLA2G6-associated neurodegeneration (PLAN) and is rarely seen in mitochondrial protein associated neurodegeneration (MPAN). Mutation analysis of PLA2G6 showed the compound heterozygous presence of the c.1021G>A (p.Ala341Thr) and c.2036G>T (p.Gly679Val) mutations in the patient, while both parents were heterozygous carriers, confirming the diagnosis of atypical NAD. This report highlights that childhood-onset gait ataxia with subtle behavioral and/or expressive speech abnormalities may be the presenting features of atypical NAD.