Magnetic resonance imaging negative myelopathy in Leber's hereditary optic neuropathy: a case report.

BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a common form of mitochondrial disease. The typical clinical presentation of LHON is subacute, painless loss of vision resulting from bilateral optic nerve atrophy. Moreover, extra-ocular manifestations such as cardiac conduction abnormalities and neurological manifestations such as multiple sclerosis (MS) like disease or parkinsonism are encountered in some patients. Abnormal findings in spinal cord MR imaging or in the cerebrospinal fluid (CSF) have been observed in previous cases of LHON-associated myelopathy. CASE PRESENTATION: We report a male patient with LHON who developed symptoms of myelopathy including gait unsteadiness, enhanced deep tendon reflexes and sensory loss of the lower extremities. Imaging of the brain and spinal cord, CSF analysis, as well as neurography and electromyography did not disclose any abnormalities. The somatosensory evoked potential (SEP) findings were suggestive of dorsal column dysfunction. CONCLUSIONS: The patient case demonstrates that myelopathy associated with LHON can present without abnormal findings in central nervous system MR imaging or in the CSF, and without evidence suggestive of multiple sclerosis or MS-like disease. The dorsal column seems to be particularly vulnerable to myelopathy changes in LHON. Evoked potential investigations may assist in confirming the diagnosis, when clinical features are in line with myelopathy but findings in CSF analysis and central nervous system imaging are normal.

Validation of the Finnish Version of the Unified Dyskinesia Rating Scale.

INTRODUCTION: The Unified Dyskinesia Rating Scale (UDysRS) was developed to provide a comprehensive rating tool of dyskinesia in Parkinson's disease (PD). Because dyskinesia therapy trials involve multicenter studies, having a scale that is validated in multiple non-English languages is pivotal to international efforts to treat dyskinesia. The aim of the present study was to organize and perform an independent validation of the UDysRS Finnish version. METHODS: The UDysRS was translated into Finnish and then back-translated into English using 2 independent teams. Cognitive pretesting was conducted on the Finnish version and required modifications to the structure or wording of the translation. The final Finnish version was administered to 250 PD patients whose native language is Finnish. The data were analyzed to assess the confirmatory factor structure to the Spanish UDysRS (the reference standard). Secondary analyses included an exploratory factor analysis (EFA), independent of the reference standard. RESULTS: The comparative fit index (CFI), in comparison with the reference standard factor structure, was 0.963 for Finnish. In the EFA, where variability from sample to sample is expected, isolated item differences of factor structure were found between the Finnish and Reference Standard versions of the UDysRS. These subtle differences may relate to differences in sample composition or variations in disease status. CONCLUSION: The overall factor structure of the Finnish version was consistent with that of the reference standard, and it can be designated as the official version of the UDysRS for Finnish speaking populations.

Pathogenic variants in MT-ATP6: A United Kingdom-based mitochondrial disease cohort study.

Distinct clinical syndromes have been associated with pathogenic MT-ATP6 variants. In this cohort study, we identified 125 individuals (60 families) including 88 clinically affected individuals and 37 asymptomatic carriers. Thirty-one individuals presented with Leigh syndrome and 7 with neuropathy ataxia retinitis pigmentosa. The remaining 50 patients presented with variable nonsyndromic features including ataxia, neuropathy, and learning disability. We confirmed maternal inheritance in 39 families and demonstrated that tissue segregation patterns and phenotypic threshold are variant dependent. Our findings suggest that MT-ATP6-related mitochondrial DNA disease is best conceptualized as a mitochondrial disease spectrum disorder and should be routinely included in genetic ataxia and neuropathy gene panels. ANN NEUROL 2019;86:310-315.

Mitochondrial DNA variation in sudden cardiac death: a population-based study.

Cardiomyopathy and cardiac conduction defects are common manifestations of mitochondrial disease. Previous studies suggest that clinically asymptomatic individuals harbouring pathogenic mitochondrial DNA (mtDNA) mutations in the cardiac muscle may have sudden cardiac death (SCD) as the first manifestation of mitochondrial disease. We investigated the contribution of pathogenic mtDNA point mutations and mtDNA haplogroups in cardiac muscle in a cohort of 280 Finnish subjects that had died from non-ischaemic SCD with the median age of death at 59 years and in 537 population controls. We did not find any common or novel pathogenic mutations, but the frequency of haplogroup H1 was higher in the SCD subjects than that in 537 population controls (odds ratio: 1.76, confidence interval 95%: 1.02-3.04). We conclude that, at the population level, pathogenic point mutations in mtDNA do not contribute to non-ischaemic SCD, but natural variation may modify the risk.

Mitochondrial disease: mimics and chameleons.

Mitochondrial diseases are inherited disorders of oxidative phosphorylation that present with a multitude of clinical features in different combinations and with various inheritance patterns. To complicate the issue further, the clinical features of mitochondrial disorders overlap with common neurological and non-neurological diseases. This presents a diagnostic challenge: when is a rare mitochondrial disease responsible for a more 'common or garden' neurological presentation, and how often are neurologists missing them in routine clinical practice? Here, we briefly review some common clinical features associated with mitochondrial disease, and provide some clues as to how patients with these mitochondrial disorders might be identified. We discuss both 'chameleons'-mitochondrial disorders that may look like something else, and 'mimics'-other conditions that may clinically resemble mitochondrial disease. The diagnosis sometimes needs highly specialised tests, but the advent of 'next generation' sequencing will simplify the clinical approach over the next few years.

[Phenotype and incidence of Creutzfeldt-Jakob disease in Finland in 1997-2013]. / Creutzfeldt-Jakobin taudin ilmiasu ja ilmaantuvuus Suomessa vuosina 1997-2013.

INTRODUCTION: The incidence of Creutzfeldt-Jakob disease (CJD) in Finland in 1974-1989 was reported to be 0.6/1 000 000. Our aim was to compare the current incidence of CJD in Finland with the earlier incidence and also study the diagnostics of the disease. METHODS: Register study of the Finnish CJD cases from 1997 to 2012 and the clinical data of CJD patients within the Hospital District of Southwest Finland from 2007 to 2013. RESULTS: There were 119 cases. The average yearly incidence was 1.36-1.44/1 000 000. CONCLUSIONS: Compared with the previous study, the incidence in Finland appears to have increased. The change is propably due to increased awareness and improved diagnostic methods.

Constant high adrenal FDG uptake in PET/CT associated with mitochondrial disease.

We describe a patient with the m.3243A>G mitochondrial DNA mutation who developed sepsis caused by Streptococcus constellatus. In the acute phase of illness, abnormally high uptake of (18)F-FDG was observed in both adrenal glands that appeared anatomically normal. In repeated imaging six months later the adrenal uptake had diminished but remained clearly elevated. We did not observe high adrenal FDG uptake as in the patient described here among 30 patients with Staphylococcus aureus sepsis that were investigated with identical imaging protocol. In sepsis, oxygen consumption and metabolic rate are increased compared to normal metabolism. The observed high adrenal FDG uptake during sepsis in this patient probably reflects the acute metabolic stress induced by the infection. Interestingly, in repeated imaging six months later, the adrenal SUVs had diminished but were still abnormally high: this suggests constant high levels of metabolic stress associated with the mitochondrial disorder.

Brain ¹8F-FDG and ¹¹C-PiB PET findings in two siblings with FTD/ALS associated with the C9ORF72 repeat expansion.

The C9ORF72 hexanucleotide expansion is a major pathological expansion pattern found in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (C9FTD/ALS). We describe a patient in whom early clinical evaluation, MRI and fluorodeoxyglucose (FDG) positron emission tomography (PET) findings failed to definitively differentiate between FTD and Alzheimer's disease (AD), whereas (11)C-Pittsburgh compound B (PiB) PET was negative for amyloid pathology. He later developed ALS symptoms, and post mortem neuropathological findings were diagnostic of FTD-ALS, while no findings suggested AD. His sister was diagnosed with FTD, and the C9ORF72 expansion was detected in both siblings. We conclude that ¹¹C-PiB PET imaging may help the early differential diagnosis between AD and FTD, including C9FTD/ALS.

Incidence and prevalence of mtDNA-related adult mitochondrial disease in Southwest Finland, 2009-2022: an observational, population-based study.

Background: Mitochondrial diseases are common inherited metabolic disorders. Due to improved case ascertainment and diagnosis methods, the detection of new diagnoses of mitochondrial disease can be expected to increase. In December 2009, the prevalence of mitochondrial DNA (mtDNA)-related mitochondrial disease was 4.6/100 000 (95% CI, 2.7 to 7.2) in the adult population of Southwest Finland. We investigated the number of new diagnoses and the incidence of mitochondrial disease in Southwest Finland between December 2009 and December 2022. Methods: We collected data on all adult patients from Southwest Finland diagnosed with mitochondrial disease on 31 December 2009 and 31 December 2022. Most patients had been diagnosed at the Turku University Hospital (TUH) neurology outpatient clinic. Patients were also identified by searching the TUH electronic patient database for relevant International Classification of Diseases, Tenth Revision codes and conducted mtDNA analyses. Results: 42 new patients were diagnosed giving a mean annual rate of 3.2 new diagnoses. In 2022, the minimum prevalence estimate of adult mtDNA-related mitochondrial disease was 9.2/100 000 (95% CI, 6.5 to 12.7). The prevalence of adult mtDNA disease associated with m.3243A>G was 4.2/100 000 (95% CI, 2.5 to 6.7), and that with large-scale mtDNA deletions was 1.3/100 000 (95% CI, 0.4 to 2.9). During the 13-year period, the annual incidence of adult mtDNA disease was 0.6/100 000 and that of adult m.3243A>G-related disease 0.3/100 000. Conclusion: Our results suggest that improved means of diagnostics and dedicated effort increase the detection of mitochondrial disease.

Novel SLC18A2 Variant in Infantile Dystonia-Parkinsonism Type 2.

Infantile dystonia-parkinsonism type 2 (PKDYS2) is a rare inherited autosomal recessive movement disorder with onset in infancy. The disease is associated with a mutation in the solute carrier family 18 member A2 gene (SLC18A2). There are reports of trials with dopaminergic drugs and the condition of patients given levodopa almost always worsens and dopamine agonists give varying degrees of benefit to some. Here, we report a PKDYS2 patient with a new variant in the SLC18A2 gene who underwent multiple trials of pharmacotherapy. The abnormalities in development and neurological examination of the case were first noted at the age of 2 months, and after a series of treatment attempts (e.g., with antiepileptics) and diagnostic procedures, the diagnosis of PKDYS2 was determined when whole exome sequencing (WES) at age 6, revealed a homozygous pathologic variant NM_003054.4:c.1107dup, p.(Val370Serfs∗91) in the SLC18A2 gene. The patient then received treatment with multiple dopaminergic drugs (e.g., levodopa, pramipexole, and methylphenidate). The patient with PKDYS2 harbored a new variant in SLC18A2. The phenotype of the patient resembles that of some previously reported patients with PKDYS2. The patient received minor benefits from certain dopaminergic drugs, such as pramipexole, but side effects led to the discontinuation of tested medications.

WFS1 variants in Finnish patients with diabetes mellitus, sensorineural hearing impairment or optic atrophy, and in suicide victims.

Mutations in the wolframin gene, WFS1, cause Wolfram syndrome, a rare recessive neurodegenerative disorder. The clinical features include early-onset bilateral optic atrophy (OA), diabetes mellitus (DM), diabetes insipidus, hearing impairment, urinary tract abnormalities and psychiatric illness, and, furthermore, WFS1 variants appear to be associated with non-syndromic DM and hearing impairment. Variation of WFS1 was investigated in Finnish subjects consisting 182 patients with DM, 117 patients with sensorineural hearing impairment (SNHI) and 44 patients with OA, and in 95 suicide victims. Twenty-two variants were found in the coding region of WFS1, including three novel nonsynonymous variants. The frequency of the p.[His456] allele was significantly higher in the patients with SNHI (11.5%; corrected P=0.00008), DM (6.6%; corrected P=0.036) or OA (9.1%; corrected P=0.043) than that in the 285 controls (3.3%). The frequency of the p.[His611] allele was 55.8% in the patients with DM being higher than that in the controls (47%; corrected P=0.039). The frequencies of p.[His456] and p.[His611] were similarly increased in an independent group of patients with DM (N=299). The results support previous findings that genetic variation of WFS1 contributes to the risk of DM and SNHI.

Detection of human herpesvirus 7 DNA from the CSF in association with neurosarcoidosis.

This study reports a previously healthy, immunocompetent adult male in whom human herpesvirus 7 (HHV-7) DNA was detected continuously from the cerebrospinal fluid (CSF). This patient developed definite sarcoidosis with primary symptomatic manifestations in the central nervous system (CNS). The initial presentation was with loss of visual acuity and papilledema. Brain MR imaging at presentation confirmed papilledema, but otherwise there were no focal abnormalities or signs of hydrocephalus. CSF investigation revealed pleocytosis and elevated protein levels. HHV-7 DNA was detected repeatedly from CSF but not from blood over 1 year follow-up. High resolution computed tomography of lungs was normal. Positron emission tomography showed several metabolically active lymph nodes in the mediastinum, and the histopathological investigation revealed granulomatous inflammation consistent with sarcoidosis. The finding of HHV-7 DNA in the CSF in the context of neurosarcoidosis has not been reported previously. The detection of HHV-7 DNA may result from the selective activation of CD4+ T-lymphocytes in the CSF caused by neurosarcoidosis. Further studies are needed to establish whether the detection of HHV-7 DNA in the CSF in association with neurosarcoidosis represents a clinically significant HHV-7 CNS infection.

Progressive external ophthalmoplegia in southwestern Finland: a clinical and genetic study.

BACKGROUND: Progressive external ophthalmoplegia (PEO) is a common phenotype of mitochondrial disease. Molecular etiologies include sporadic, large-scale deletions in mitochondrial DNA (mtDNA), multiple mtDNA deletions secondary to autosomal dominant or recessive mutations and mtDNA point mutations. METHODS: We studied the prevalence and clinical and genetic characteristics of PEO in a defined population in southwestern Finland. A total of 620 patients were first identified from the patient registry at the Turku University Hospital over an 18-year period. The medical records of these patients were scrutinized, and those with clinical features compatible with PEO were ascertained. RESULTS: We identified 10 patients with possible PEO. The patients were examined clinically, and DNA was analyzed for mtDNA deletions and for the m.3243A>G and m.8344A>G mtDNA point mutations. The ANT1, PEO1, POLG1 and POLG2 genes were sequenced. We confirmed the clinical diagnosis of PEO in 6 patients. Large-scale mtDNA deletions were detected in 3 out of 6 PEO patients and mutations in the POLG1 gene in 1 out of 6. We did not find any mutations in the ANT1, PEO1 or POLG2 genes. CONCLUSIONS: Our results suggest that molecular investigation of patients with PEO, either sporadic or familial, should start with an analysis for mtDNA deletions, followed by an analysis of the POLG1 gene.

Successful treatment of POLG-related mitochondrial epilepsy with antiepileptic drugs and low glycaemic index diet.

Epilepsy is a common manifestation of mitochondrial disease associated with mutations of the mitochondrial polymerase γ (POLG). Prognosis of mitochondrial epilepsy is often poor and there are few reports of successful treatment of POLG-related epilepsy. We describe a 26-year-old woman who experienced severe headache during a three-day period, followed by symptoms of visual flashing, speech difficulty, and generalised seizures. EEG recording showed non-convulsive status epilepticus (left occipital area) and brain MRI revealed parieto-occipital T2-hyperintensities. Visual aura and aphasia persisted despite antiepileptic medication with phenytoin, oxcarbazepine, and levetiracetam. Mitochondrial disorder was clinically suspected and a homozygous c.2243G>C mutation (p.Trp748Ser) was discovered in the POLG1 gene. The patient was then set on a low glycaemic index treatment (LGIT) variant of the ketogenic diet, after which the headaches, aphasia, and visual aura progressively improved and disappeared. She returned home two weeks after onset of symptoms and has not had further seizures. She continues to receive levetiracetam monotherapy and LGIT. We conclude that, at least for this patient, the combination of three antiepileptic drugs and LGIT is effective and well tolerated as treatment for severe episodes of POLG-related mitochondrial epilepsy.

Rapid improvement of a complex migrainous episode with sodium valproate in a patient with CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease of small arteries caused by mutations in the Notch3 gene. Complex migrainous episodes, such as acute confusional migraine, status migrainosus with persisting aura, and "CADASIL coma" have been described in patients with CADASIL. However, there are few descriptions of effective treatment of such episodes. We describe a 44-year-old male with CADASIL, who presented with sudden-onset aphasia and decreased responsiveness after prolonged, severe migraine attack. Subsequently, the patient had two generalized seizures. A subtle status epilepticus was suspected because of drowsiness and seizures, and intravenous sodium valproate medication was initiated. EEG recording showed left hemispheric attenuation but no spike discharges, thus not confirming epileptic mechanism. The clinical status of the patient improved markedly after the initiation of valproate. The patient started speaking again; drowsiness and headache subsided. In repeated EEG recording, the left hemispheric attenuation disappeared. Diffusion weighted MR imaging showed no signs of recent ischemic events. The patient recovered fully from the episode with no further seizures. We suggest that CADASIL patients with acute complex migrainous episodes may benefit from intravenous sodium valproate.

Deep brain stimulation for monogenic Parkinson's disease: a systematic review.

Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD) patients with motor fluctuations and dyskinesias. The key DBS efficacy studies were performed in PD patients with unknown genotypes; however, given the estimated monogenic mutation prevalence of approximately 5-10%, most commonly LRRK2, PRKN, PINK1 and SNCA, and risk-increasing genetic factors such as GBA, proper characterization is becoming increasingly relevant. We performed a systematic review of 46 studies that reported DBS effects in 221 genetic PD patients. The results suggest that monogenic PD patients have variable DBS benefit depending on the mutated gene. Outcome appears excellent in patients with the most common LRRK2 mutation, p.G2019S, and good in patients with PRKN mutations but poor in patients with the more rare LRRK2 p.R1441G mutation. The overall benefit of DBS in SNCA, GBA and LRRK2 p.T2031S mutations may be compromised due to rapid progression of cognitive and neuropsychiatric symptoms. In the presence of other mutations, the motor changes in DBS-treated monogenic PD patients appear comparable to those of the general PD population.

Consensus-based statements for the management of mitochondrial stroke-like episodes.

Background: Focal-onset seizures and encephalopathy are prominent features of a stroke-like episode, which is a severe neurological manifestation associated with subtypes of mitochondrial disease. Despite more than 30 years of research, the acute treatment of stroke-like episodes remains controversial. Methods: We used the modified Delphi process to harness the clinical expertise of a group of mitochondrial disease specialists from five European countries to produce consensus guidance for the acute management of stroke-like episodes and commonly associated complications. Results: Consensus on a new definition of mitochondrial stroke-like episodes was achieved and enabled the group to develop diagnostic criteria based on clinical features, neuroimaging and/or electroencephalogram findings. Guidelines for the management of strokelike episodes were agreed with aggressive seizure management strongly recommended at the outset of stroke-like episodes. Conclusions: Our consensus statement defines stroke-like episodes in terms of an epileptic encephalopathy and we have used this to revise both diagnostic criteria and guidelines for management. A prospective, multi-centre, randomised controlled trial is required for evaluating the efficacy of any compound on modifying the trajectory of stroke-like episodes.

The m.7510T>C mutation: Hearing impairment and a complex neurologic phenotype.

Objectives: Mutations in mitochondrial DNA cause a variety of clinical phenotypes ranging from a mild hearing impairment (HI) to severe encephalomyopathy. The MT-TS1 gene is a hotspot for mutations causing HI. The m.7510T>C mutation in MT-TS1 has been previously associated with non-syndromic HI in four families from different ethnic backgrounds. Materials and Methods: We describe the clinical, genetic, and histopathological findings in a Finnish family with the heteroplasmic m.7510T>C mutation in mitochondrial DNA. Results: The family proband presented with a progressive mitochondrial disease phenotype including migraine, epilepsy, mild ataxia, and cognitive impairment in addition to HI. One young adult presented with HI only. Other family members had a mild phenotype comprising ataxia and tremor in addition to HI. Mutation heteroplasmy was 90% in the blood of maternal grandmother and ≥99% in the muscle and blood of the three other family members. Muscle histology was consistent with mitochondrial myopathy in three family members. The mitochondrial haplogroup of the family was a different branch of the haplogroup H than in the previous reports of this mutation. Conclusion: Our results suggest that, in addition to sensorineural HI, the m.7510T>C mutation is associated with a spectrum of mitochondrial disease clinical features including migraine, epilepsy, cognitive impairment, ataxia, and tremor, and with evidence of mitochondrial myopathy.