Mitochondrial Depletion Syndrome Research Articles

The clinical and radiological profile of primary lateral sclerosis: a population-based study.

Primary lateral sclerosis is a progressive upper-motor-neuron disorder associated with markedly longer survival than ALS. In contrast to ALS, the genetic susceptibility, histopathological profile and imaging signature of PLS are poorly characterised. Suspected PLS patients often face considerable diagnostic delay and prognostic uncertainty. To characterise the distinguishing clinical, genetic and imaging features of PLS in contrast to ALS and healthy controls. A prospective population-based study was conducted with 49 PLS patients, 100 ALS patients and 100 healthy controls using genetic profiling, standardised clinical assessments and neuroimaging. Whole-brain and region-of-interest analyses were undertaken to evaluate patterns of grey and white matter degeneration. In PLS, disease burden in the motor cortex is more medial than in ALS consistent with its lower limb symptom-predominance. PLS is associated with considerable cerebellar white and grey matter degeneration and the extra-motor profile of PLS includes marked insular, inferior frontal and left pars opercularis pathology. Contrary to ALS, PLS spares the postcentral gyrus. The body and splenium of the corpus callosum are preferentially affected in PLS, in contrast to the genu involvement observed in ALS. Clinical measures show anatomically meaningful correlations with imaging metrics in a somatotopic distribution. PLS patients tested negative for C9orf72 repeat expansions, known ALS and HSP-associated genes. Multiparametric imaging in PLS highlights disease-specific motor and extra-motor involvement distinct from ALS. In a condition where limited post-mortem data are available, imaging offers invaluable pathological insights. Anatomical correlations with clinical metrics confirm the biomarker potential of quantitative neuroimaging in PLS.

Deoxythymidylate kinase, DTYMK, is a novel gene for mitochondrial DNA depletion syndrome

BackgroundMitochondrial DNA depletion syndrome is a group of heterogeneous diseases with non-specific presentation. The common feature is the quantitative depletion of mitochondrial DNA without qualitative defects. Diagnosis of these diseases poses a challenge and whole exome sequencing is often needed for their diagnoses. CaseTwo siblings of a quartet family, presenting with hypotonia, microcephaly and severe intellectual disability, have been diagnosed to harbor two heterozygous variants in trans in the DTYMK gene of the thymidine biosynthesis pathway. Mitochondrial DNA depletion has been demonstrated in silico in the more severe sibling. ConclusionsWe suggest the consideration of incorporating DTYMK as one of the associated genes of mitochondrial DNA depletion syndrome (MDDS). DTYMK may be the missing link in the mitochondrial nucleotide salvage pathway but further characterization and additional evidence would be needed.

Presymptomatic spinal cord pathology in c9orf72 mutation carriers: A longitudinal neuroimaging study.

C9orf72 hexanucleotide repeats expansions account for almost half of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases. Recent imaging studies in asymptomatic C9orf72 carriers have demonstrated cerebral white (WM) and gray matter (GM) degeneration before the age of 40 years. The objective of this study was to characterize cervical spinal cord (SC) changes in asymptomatic C9orf72 hexanucleotide carriers. Seventy-two asymptomatic individuals were enrolled in a prospective study of first-degree relatives of ALS and FTD patients carrying the c9orf72 hexanucleotide expansion. Forty of them carried the pathogenic mutation (C9+ ). Each subject underwent quantitative cervical cord imaging. Structural GM and WM metrics and diffusivity parameters were evaluated at baseline and 18 months later. Data were analyzed in C9+ and C9- subgroups, and C9+ subjects were further stratified by age. At baseline, significant WM atrophy was detected at each cervical vertebral level in C9+ subjects older than 40 years without associated changes in GM and diffusion tensor imaging parameters. At 18-month follow-up, WM atrophy was accompanied by significant corticospinal tract (CST) fractional anisotropy (FA) reductions. Intriguingly, asymptomatic C9+ subjects older than 40 years with family history of ALS (as opposed to FTD) also exhibited significant CST FA reduction at baseline. Cervical SC imaging detects WM atrophy exclusively in C9+ subjects older than 40 years, and progressive CST FA reductions can be identified on 18-month follow-up. Cervical SC magnetic resonance imaging readily captures presymptomatic pathological changes and disease propagation in c9orf72-associated conditions. ANN NEUROL 2019;86:158-167.

Identification and Characterization of New RNASEH1 Mutations Associated With PEO Syndrome and Multiple Mitochondrial DNA Deletions.

Mitochondrial DNA (mtDNA) depletion and deletion syndrome encompasses a group of disorders caused by mutations in genes involved in mtDNA replication and maintenance. The clinical phenotype ranges from fatal infantile hepatocerebral forms to mild adult onset progressive external ophthalmoplegia (PEO). We report the case of a patient with PEO and multiple mtDNA deletions, with two new homozygous mutations in RNASEH1. The first mutation (c.487T>C) is located in the same catalytic domain as the four previously reported mutations, and the second (c.258_260del) is located in the connection domain, where no mutations have been reported. In silico study of the mutations predicted only the first mutation as pathogenic, but functional studies showed that both mutations cause loss of ribonuclease H1 activity. mtDNA replication dysfunction was demonstrated in patient fibroblasts, which were unable to recover normal mtDNA copy number after ethidium bromide-induced mtDNA depletion. Our results demonstrate the pathogenicity of two new RNASEH1 variants found in a patient with PEO syndrome, multiple deletions, and mild mitochondrial myopathy.

Network spread determines severity of degeneration and disconnection in Huntington's disease.

Trans-neuronal propagation of mutant huntingtin protein contributes to the organised spread of cortico-striatal degeneration and disconnection in Huntington's disease (HD). We investigated whether the network diffusion model, which models transneuronal spread as diffusion of pathological proteins via the brain connectome, can determine the severity of neural degeneration and disconnection in HD. We used structural magnetic resonance imaging (MRI) and high-angular resolution diffusion weighted imaging (DWI) data from symptomatic Huntington's disease (HD) (N = 26) and age-matched healthy controls (N = 26) to measure neural degeneration and disconnection in HD. The network diffusion model was used to test whether disease spread, via the human brain connectome, is a viable mechanism to explain the distribution of pathology across the brain. We found that an eigenmode identified in the healthy human brain connectome Laplacian matrix, accurately predicts the cortico-striatal spatial pattern of degeneration in HD. Furthermore, the spread of neural degeneration from sub-cortical brain regions, including the accumbens and thalamus, generates a spatial pattern which represents the typical neurodegenerative characteristics in HD. The white matter connections connecting the nodes with the highest amount of disease factors, when diffusion based disease spread is initiated from the striatum, were found to be most vulnerable to disconnection in HD. These findings suggest that trans-neuronal diffusion of mutant huntingtin protein across the human brain connectome may explain the pattern of gray matter degeneration and white matter disconnection that are hallmarks of HD.

P84-F Subacute polyneuropathy partially responsive to immunomodulatory treatment coexisting with POLG mutation

Background During the last few years, the correlation between mitochondrial disorders and autoimmune diseases has been reported. Autoimmune polyneuropathies were concomitant with symptoms related to the polymerase γ (POLG) mutations. POLG is involved in mitochondrial DNA (mtDNA) replication and maintenance. Material and methods We present a case of a16-year-old girl with W748S mutation of POLG region with a 1,5-year history of slowly progressive walking difficulties. Results In the neurological examination the girl had ataxic gait with sensory disturbances in lower extremities with areflexia. Nerve conduction studies (NCS) demonstrated axonal–demyelinating sensorimotor polyneuropathy of the lower limbs. Additionally, magnetic resonance imaging (MRI) of the lumbar spine revealed gadolinium enhancement of the spinal roots and an examination of cerebrospinal fluid showed dissemination. The immunomodulatory treatment with intravenous methylprednisolone and intravenous immunoglobulin (IVIg) was started. Conclusions The IVIg and IVMP treatment led to marked improvement of her abnormal gait and improved resolution of abnormalities of touch, temperature sensation and improved proprioception. The W748S mutations were commonly reported and associated with variable phenotypes, most often Alpers syndrome, but also polyneuropathy. However, electrodiagnostic features and partial response to immunomodulatory therapy suggest the autoimmune etiology of the patients’ subacute symptoms. We hypothesize that oxidative stress caused by impaired mitochondria function may trigger an autoimmune response.

Medial Temporal Lobe Disconnection and Hyperexcitability Across Alzheimer's Disease Stages.

The posteromedial cortex (PMC) and medial temporal lobes (MTL) are two brain regions particularly vulnerable in Alzheimer’s disease (AD). We have reviewed the spatiotemporal patterns of amyloid-β and tau accumulation, local MTL functional alterations and MTL-PMC network reconfiguration, and propose a model to relate these elements to each other. Functional and structural MTL-PMC disconnection happen concomitant with amyloid-β plaques and neurofibrillary tau accumulation within these same regions. Ongoing disconnection is accompanied by dysfunctional intrinsic local MTL circuit hyperexcitability, which exacerbates across distinct clinical stages of AD. Our overarching model proposes a sequence of events relating the spatiotemporal patterns of amyloid-β and tau accumulation to MTL-PMC disconnection and local MTL hyperexcitability. We hypothesize that cortical PMC amyloid-β pathology induces long-range information processing deficits through functional and structural MTL-PMC dysconnectivity at early disease stages, which in turn drives local MTL circuit hyperexcitability. Intrinsic local MTL circuit hyperexcitability subsequently accelerates local age-related tau deposition, facilitating tau spread from the MTL to the PMC, eventually resulting in extensive structural degeneration of white and grey matter as the disease advances. We hope that the present model may inform future longitudinal studies needed to test the proposed sequence of events.

Phenotype and genotype of twelve Chinese children with mitochondrial DNA depletion syndromes

Objective: To explore the phenotype and genotype of mitochondrial DNA depletion syndromes (MDS) in Chinese children. Methods: The clinical and genetic data of 12 MDS patients (8 were boys and 4 were girls) diagnosed in the Department of Neurology in Beijing Children's Hospital, Capital Medical University from October 2010 to April 2018 were retrospectively collected and analyzed. Results: The developmental milestones were normal or mildly retardated before disease onset. The age of onset ranged from 0 to 2.9-year-old. Most cases developed postnatal or after infection. The most common initial symptoms were feeding difficulty, seizure, muscle weakness, psychomotor regression and hepatic dysfunction. At the last evaluation, all the patients had developmental retardation, failure to thrive, muscle weakness, and dysphagia. Other clinical features were weight loss (9 cases), hearing impairment (7 cases), ptosis (6 cases), seizure (5 cases), dyspnea (4 cases), visual impairment (1 case), hirsutism (1 case), lactic acidosis (7 cases), elevated hepatic enzymes (4 cases) and creatine kinase (2 cases), elevated protein in cerebrospinal fluid (3 cases), abnormalities on screening for inborn error of metabolism (10 cases) and brain magnetic resonance imaging (MRI) (10 cases), abnormal electromyogram (including neurogenic or myogenic injury) (5 cases). Five patients died of infection or multiple organ failure. A total of 18 novel mutations presented below were detected in these patients. Among the 6 cases of encephalomyopathy, there were 3 with SUCLG1 mutation (c. 916G>T, c. 619T>C, c. 980dupT were novel), 2 with SUCLA2 mutation (c. 851G>A, c.971G>A were novel), and one with RRM2B mutation (c.456-2A>G, c.212T>C were novel). All the cases of hepatic encephalopathy all had POLG mutations (c. 3151G>A, c. 2294C>T, c. 2858G>C, c. 680G>A and c. 150_158delGCAGCAGCA were novel). Two cases of infantile-onset spinocerebellar ataxia had TWNK mutations (c. 1163C>T, c. 1319T>C, c. 1388G>A and c. 257_258delAG were novel). One case of myopathy had TK2 mutations (c.557C>G and c.341A>T were novel). Conclusions: The clinical and genetic features of MDS were heterogeneous. Eighteen novel mutations in six MDS related genes were reported, which expanded the genetic spectrum of MDS in Chinese children.

Study progress of mitochondrial DNA depletion syndromes

Mitochondrial DNA(mtDNA) depletion syndromes (MDS) is a type of autosomal recessive genetic disease characterized by a severe reduction in mtDNA content caused by mutations in the nuclear gene, which results in impaired energy production in affected tissues and organs.According to phenotype, MDS are usually classified as 4 forms: myopathic, encephalomyopathic, hepa-tocerebarl and neurogastrointestinal.The following 9 types of related genes have been reported: a myopathic form associated with mutations in TK2; an encephalomyopathic form associated with mutations in SUCLA2, SUCLG1, or RRM2B; a hepa-tocerebral form associated with mutations in DGUOK, MPV17, POLG, or C10orf2; and a neurogastrointestinal form associated with mutations in TYMP.Some MDS can lead to early death in newborns and infants, so early identification is very important.Combination of biochemical testing, histopathology, respiratory chain complex testing and mtDNA quantification is needed for the diagnosis.The final diagnosis requires genetic testing. Key words: Mitochondrial DNA depletion syndrome; Mitochondrial gene; Diagnosis

Tau PET in autosomal dominant Alzheimer's disease: relationship with cognition, dementia and other biomarkers.

Tauopathy is a hallmark pathology of Alzheimer's disease with a strong relationship with cognitive impairment. As such, understanding tau may be a key to clinical interventions. In vivo tauopathy has been measured using cerebrospinal fluid assays, but these do not provide information about where pathology is in the brain. The introduction of PET ligands that bind to paired helical filaments provides the ability to measure the amount and distribution of tau pathology. The heritability of the age of dementia onset tied to the specific mutations found in autosomal dominant Alzheimer's disease families provides an elegant model to study the spread of tau across the course of the disease as well as the cross-modal relationship between tau and other biomarkers. To better understand the pathobiology of Alzheimer's disease we measured levels of tau PET binding in individuals with dominantly inherited Alzheimer's disease using data from the Dominantly Inherited Alzheimer Network (DIAN). We examined cross-sectional measures of amyloid-β, tau, glucose metabolism, and grey matter degeneration in 15 cognitively normal mutation non-carriers, 20 asymptomatic carriers, and 15 symptomatic mutation carriers. Linear models examined the association of pathology with group, estimated years to symptom onset, as well as cross-modal relationships. For comparison, tau PET was acquired on 17 older adults with sporadic, late onset Alzheimer disease. Tau PET binding was starkly elevated in symptomatic DIAN individuals throughout the cortex. The brain areas demonstrating elevated tau PET binding overlapped with those seen in sporadic Alzheimer's disease, but with a greater cortical involvement and greater levels of binding despite similar cognitive impairment. Tau PET binding was elevated in the temporal lobe, but the most prominent loci of pathology were in the precuneus and lateral parietal regions. Symptomatic mutation carriers also demonstrated elevated tau PET binding in the basal ganglia, consistent with prior work with amyloid-β. The degree of tau tracer binding in symptomatic individuals was correlated to other biomarkers, particularly markers of neurodegeneration. In addition to the differences seen with tau, amyloid-β was increased in both asymptomatic and symptomatic groups relative to non-carriers. Glucose metabolism showed decline primarily in the symptomatic group. MRI indicated structural degeneration in both asymptomatic and symptomatic cohorts. We demonstrate that tau PET binding is elevated in symptomatic individuals with dominantly inherited Alzheimer's disease. Tau PET uptake was tied to the onset of cognitive dysfunction, and there was a higher amount, and different regional pattern of binding compared to late onset, non-familial Alzheimer's disease.

β-Synuclein-reactive T cells induce autoimmune CNS grey matter degeneration.

The grey matter is a central target of pathological processes in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. The grey matter is often also affected in multiple sclerosis, an autoimmune disease of the central nervous system. The mechanisms that underlie grey matter inflammation and degeneration in multiple sclerosis are not well understood. Here we show that, in Lewis rats, T cells directed against the neuronal protein β-synuclein specifically invade the grey matter and that this is accompanied by the presentation of multifaceted clinical disease. The expression pattern of β-synuclein induces the local activation of these T cells and, therefore, determined inflammatory priming of the tissue and targeted recruitment of immune cells. The resulting inflammation led to significant changes in the grey matter, which ranged from gliosis and neuronal destruction to brain atrophy. In humans, β-synuclein-specific T cells were enriched in patients with chronic-progressive multiple sclerosis. These findings reveal a previously unrecognized role of β-synuclein in provoking T-cell-mediated pathology of the central nervous system.

Metabolic liver diseases presenting with neonatal cholestasis: at the crossroad between old and new paradigms.

Metabolic liver diseases (MLD) are an important group of disorders presenting with neonatal cholestasis (NC). The spectrum of liver involvement is wide and the presumptive diagnosis is traditionally based on clinical and laboratory findings. Recently, next-generation sequencing (NGS) panels have emerged as an appealing tool to diagnose neonatal/infantile cholestatic disorders. The aim of this study was to identify clinical phenotypes of liver injury and contribute to find a diagnostic methodology that integrates new molecular diagnostic tools. We retrospectively analyzed the clinical and biochemical features of 16 patients with MLD and NC. Patients were categorized into three groups: A-NC with liver failure (N = 8): tyrosinemia type I (n = 2), classic galactosemia (n = 5), mitochondrial DNA depletion syndrome (n = 1); B-NC evolving with chronic liver disease (N = 5): argininemia (n = 2); mitochondrial cytopathy (n = 1); congenital disorders of glycosylation type Ia (n = 1); Zellweger syndrome (n = 1); and C-transient NC (N = 3): Niemann-Pick type C (n = 2), citrullinemia type II(n = 1).Conclusion: MLD presenting with NC can be categorized into three main clinical phenotypes of liver injury. We highlight transient NC as a clue for MLD that must be pursued. New molecular diagnostic tools can play a key role, but application criteria must be established to make them cost-effective. What is Known: • Metabolic liver diseases are an important group of disorders presenting with neonatal cholestasis. • The diagnostic approach is challenging and traditionally based on clinical and laboratory findings. Next-generation sequencing is a recent and rapidly developing tool in pediatric hepatology. What is New: • We provide a liver-targeted characterization of metabolic liver diseases presenting with neonatal cholestasis, categorizing them into three clinical phenotypes that may narrow the diagnostic possibilities. • A clinical decision-making algorithm is proposed, in which the NGS technology is integrated.

The zebrafish orthologue of the human hepatocerebral disease geneMPV17plays pleiotropic roles in mitochondria

ABSTRACTMitochondrial DNA depletion syndromes (MDS) are a group of rare autosomal recessive disorders with early onset and no cure available. MDS are caused by mutations in nuclear genes involved in mitochondrial DNA (mtDNA) maintenance, and characterized by both a strong reduction in mtDNA content and severe mitochondrial defects in affected tissues. Mutations in MPV17, a nuclear gene encoding a mitochondrial inner membrane protein, have been associated with hepatocerebral forms of MDS. The zebrafish mpv17 null mutant lacks the guanine-based reflective skin cells named iridophores and represents a promising model to clarify the role of Mpv17. In this study, we characterized the mitochondrial phenotype of mpv17−/− larvae and found early and severe ultrastructural alterations in liver mitochondria, as well as significant impairment of the respiratory chain, leading to activation of the mitochondrial quality control. Our results provide evidence for zebrafish Mpv17 being essential for maintaining mitochondrial structure and functionality, while its effects on mtDNA copy number seem to be subordinate. Considering that a role in nucleotide availability had already been postulated for MPV17, that embryos blocked in pyrimidine synthesis do phenocopy mpv17−/− knockouts (KOs) and that mpv17−/− KOs have impaired Dihydroorotate dehydrogenase activity, we provided mpv17 mutants with the pyrimidine precursor orotic acid (OA). Treatment with OA, an easily available food supplement, significantly increased both iridophore number and mtDNA content in mpv17−/− mutants, thus linking the loss of Mpv17 to pyrimidine de novo synthesis and opening a new simple therapeutic approach for MPV17-related MDS.

Severe Deoxyguanosine Kinase Deficiency in Austria: A 6-Patient Series.

Mutations in the nuclear gene DGUOK, encoding deoxyguanosine kinase, cause an infantile hepatocerebral type of mitochondrial depletion syndrome (MDS). We report 6 MDS patients harboring bi-allelic DGUOK mutations, of which 3 are novel, including a large intragenic Austrian founder deletion. One patient was diagnosed with hepatocellular carcinoma aged 6 months, supporting a link between mitochondrial DNA depletion and tumorigenesis; liver transplantation proved beneficial with regard to both tumor treatment and psychomotor development.

Neuroimaging advances in Parkinson's disease with freezing of gait: A systematic review.

Freezing of gait (FOG) is a paroxysmal gait disorder that often occurs at advanced stages of Parkinson's disease (PD). FOG consists of abrupt walking interruption and severe difficulty in locomotion with an increased risk of falling. Pathophysiological mechanisms underpinning FOG in PD are still unclear. However, advanced MRI and nuclear medicine studies have gained relevant insights into the pathophysiology of FOG in PD. Neuroimaging studies have demonstrated structural and functional abnormalities in a number of cortical and subcortical brain regions in PD patients with FOG. In this paper, we systematically review existing neuroimaging literature on the structural and functional brain changes described in PD patients with FOG, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We evaluate previous studies using various MRI techniques to estimate grey matter loss and white matter degeneration. Moreover, we review functional brain changes by examining functional MRI and nuclear medicine imaging studies. The current review provides up-to-date knowledge in this field and summarizes the possible mechanisms responsible for FOG in PD.

Liver pathology in hepato-cerebral mitochondrial depletion syndromes due to POLG1, DGUOK, 146or MPV17 variants.

Liver pathology in hepato-cerebral mitochondrial depletion syndromes due to POLG1, DGUOK, 146or MPV17 variants.

Widespread subcortical grey matter degeneration in primary lateral sclerosis: a multimodal imaging study with genetic profiling.

BackgroundPrimary lateral sclerosis (PLS) is a low incidence motor neuron disease which carries a markedly better prognosis than amyotrophic lateral sclerosis (ALS). Despite sporadic reports of extra-motor symptoms, PLS is widely regarded as a pure upper motor neuron disorder. The post mortem literature of PLS is strikingly sparse and very little is known of subcortical grey matter pathology in this condition.MethodsA prospective imaging study was undertaken with 33 PLS patients, 117 healthy controls and 100 ALS patients to specifically assess the integrity of subcortical grey matter structures and determine whether PLS and ALS have divergent thalamic, hippocampal and basal ganglia signatures. Volumetric, morphometric, segmentation and vertex-wise analyses were carried out in the three study groups to evaluate the integrity of thalamus, hippocampus, caudate, amygdala, pallidum, putamen and accumbens nucleus in each hemisphere. The hippocampus was further parcellated to characterise the involvement of specific subfields.ResultsConsiderable thalamic, caudate, and hippocampal atrophy was detected in PLS based on both volumetric and vertex analyses. Significant volume reductions were also detected in the accumbens nuclei. Hippocampal atrophy in PLS was dominated by dentate gyrus, hippocampal tail and CA4 subfield volume reductions. The morphometric comparison of ALS and PLS cohorts revealed preferential medial bi-thalamic pathology in PLS compared to the predominant putaminal degeneration detected in ALS. Another distinguishing feature between ALS and PLS was the preferential atrophy of the amygdala in ALS.ConclusionsPLS is associated with considerable subcortical grey matter degeneration and due to the extensive extra-motor involvement, it should no longer be regarded a pure upper motor neuron disorder. Given its unique pathological features and a clinical course which differs considerably from ALS, dedicated research studies and disease-specific therapeutic strategies are urgently required in PLS.

Editors' note: Right Brain: Withholding treatment from a child with an epileptic encephalomyopathy

In “Right Brain: Withholding treatment from a child with an epileptic encephalomyopathy,” Drs. Rothstein and Lewis discussed ethical considerations in the case of Charlie Gard, an infant with a mitochondrial DNA depletion syndrome whose parents unsuccessfully lobbied for him to receive an experimental therapy prior to his death in 2017. We received several responses. Dr. Sethi argues that while no effort or expense was spared to save Charlie, it is important to address the challenging but relevant dimension of utilitarian bioethics in the discussion. Similarly, Dr. Janus notes that the costs of such care should be taken into account, given limited health care resources and associated tradeoffs. Dr. Tuck also raises the added potential costs of Charlie's transfer and treatment, invoking the ethical principles of justice and fairness. In response, Drs. Rothstein and Lewis counter that Great Ormond Street Hospital's actions in Charlie's care were to spare expense, effort, and suffering of the child. They argue that economic considerations should not be the only force driving care. While acknowledging the complexity of the ethical arguments in this case, they also contend that the experimental therapy could have been appropriate with respect to the principles of beneficence, nonmaleficence, and autonomy. In “Right Brain: Withholding treatment from a child with an epileptic encephalomyopathy,” Drs. Rothstein and Lewis discussed ethical considerations in the case of Charlie Gard, an infant with a mitochondrial DNA depletion syndrome whose parents unsuccessfully lobbied for him to receive an experimental therapy prior to his death in 2017. We received several responses. Dr. Sethi argues that while no effort or expense was spared to save Charlie, it is important to address the challenging but relevant dimension of utilitarian bioethics in the discussion.

Reader response: Right Brain: Withholding treatment from a child with an epileptic encephalomyopathy.

I read with interest the Resident & Fellow Right Brain commentary by Drs. Rothstein and Lewis1 on the case of Charlie Gard. British baby Charlie Gard was at the center of a legal battle that captured the attention of the entire world in July 2017. Charlie Gard had an incurable rare genetic neuromuscular disease (mitochondrial DNA depletion syndrome), which affected his muscles and ability to breathe on his own. Doctors wished to withdraw life support, but Charlie's parents fought a prolonged legal battle to keep him alive.

The spinal and cerebral profile of adult spinal-muscular atrophy: A multimodal imaging study.

Spinal muscular atrophy (SMA) type III and IV are autosomal recessive, slowly progressive lower motor neuron syndromes. Nevertheless, wider cerebral involvement has been consistently reported in mouse models. The objective of this study is the characterisation of spinal and cerebral pathology in adult forms of SMA using multimodal quantitative imaging.MethodsTwenty-five type III and IV adult SMA patients and 25 age-matched healthy controls were enrolled in a spinal cord and brain imaging study. Structural measures of grey and white matter involvement and diffusion parameters of white matter integrity were evaluated at each cervical spinal level. Whole-brain and region-of-interest analyses were also conducted in the brain to explore cortical thickness, grey matter density and tract-based white matter alterations.ResultsIn the spinal cord, considerable grey matter atrophy was detected between C2-C6 vertebral levels. In the brain, increased grey matter density was detected in motor and extra-motor regions of SMA patients. No white matter pathology was identified neither at brain and spinal level.ConclusionsAdult forms of SMA are associated with selective grey matter degeneration in the spinal cord with preserved white matter integrity. The observed increased grey matter density in the motor cortex may represent adaptive reorganisation.