Neuronal Ceroid Lipofuscinosis Type Research Articles

MRI in CLN2 disease patients: Subtle features that support an early diagnosis.

Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare, paediatric-onset, neurodegenerative disorder characterised in its early stages by language delay, seizures and loss of motor function. It is rapidly progressive and ultimately results in the premature death of patients. We aim to highlight common magnetic resonance imaging (MRI) features seen in early CLN2 disease and increase disease awareness among clinicians in order to facilitate early diagnosis and treatment of patients with disease-modifying enzyme replacement therapy. We obtained MRI scans from 12 Turkish children with CLN2 disease, at symptom onset or time of diagnosis, and at various times during disease progression. Patient details including age at onset of symptoms, age at diagnosis and clinical presentation were collected. MRIs were analysed to identify common features present in patients with CLN2 disease. The median diagnostic delay in this cohort was 2 years, highlighting the need for increased disease awareness among clinicians. Key MRI features suggestive of CLN2 disease that were identified included cerebellar atrophy in 11 patients, linear hyperintensity of central white matter in 10 patients, cerebral atrophy in 8 patients and thinning of the corpus callosum in 6 patients. Thalamic hypointensity was seen in 1 patient and may also indicate CLN2 disease. It is important to consider the presenting symptoms alongside clinical test results in order to support early diagnosis of CLN2 disease. Clinical suspicion of CLN2 disease accompanied by the detection of any of the above-mentioned features on MRI should encourage healthcare professionals to test for CLN2 disease.

Targeted re-sequencing for early diagnosis of genetic causes of childhood epilepsy: the Italian experience from the \u2018beyond epilepsy\u2019 project

BackgroundChildhood epilepsies are a heterogeneous group of conditions differing in diagnostic criteria, management, and outcome. Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a neurodegenerative condition caused by biallelic TPP1 variants. This disorder presents with subtle and relatively non-specific symptoms, mimicking those observed in more common paediatric epilepsies and followed by rapid psychomotor deterioration and drug-resistant epilepsy. A prompt diagnosis is essential to adopt appropriate treatment and disease management strategies.MethodsThis is a prospective, multicentre study on the efficiency of targeted re-sequencing in the early identification of the genetic causes of childhood epilepsy, with particular regard to CLN2. After phenotypic characterization, a 283-gene Next Generation Sequencing panel was performed in 21 Italian children with neurodevelopmental abnormalities, aged between 24 and 60 months, experiencing first unprovoked seizure after 2 years of age.ResultsThe average age at enrolment was 39.9 months, with a mean age at seizure onset of 30.9 months and a mean time interval between seizure onset and targeted resequencing of 9 months. Genetic confirmation was achieved in 4 out of 21 patients, with a diagnostic yield of 19%. In one case, the homozygous splice acceptor variant c.509-1G > C in TPP1 was identified, leading to a CLN2 diagnosis. Three pathogenic variants in MECP2 were also detected in three patients, including the frameshift variant c.1157_1186delinsA (p.Leu386Hisfs*9) in a girl with negative single gene sequencing. Variants of unknown significance (VUS) were found in 11 out of 21 (52.4%) individuals, whereas no clinically significant variants were observed in the remaining 6 subjects.ConclusionsOur findings support the efficacy of target re-sequencing in the identification of the genetic causes of childhood epilepsy and suggest that this technique might prove successful in the early detection of CLN2 as well as other neurodevelopmental conditions.

A novel pathogenic frameshift variant unmasked by a large de novo deletion at 13q21.33-q31.1 in a Chinese patient with neuronal ceroid lipofuscinosis type 5

BackgroundNeuronal ceroid lipofuscinosis type 5 (CLN5) is a rare form of neuronal ceroid lipofuscinoses (NCLs) which are a group of inherited neurodegenerative diseases characterized by progressive intellectual and motor deterioration, visual failure, seizures, behavioral changes and premature death. CLN5 was initially named Finnish variant late infantile NCL, it is now known to be present in other ethnic populations and with variable age of onset. Few CLN5 patients had been reported in Chinese population.Case presentationIn this paper, we report the symptoms of a Chinese patient who suffer from developmental regression and grand mal epilepsy for several years. The DNA was extracted from peripheral blood of proband and both parents, and then whole exome sequencing was performed using genomic DNA. Both sequence variants and copy number variants (CNVs) were analyzed and classified according to guidelines. As the result, a novel frameshift mutation c.718_719delAT/p.Met240fs in CLN5 and a de novo large deletion at 13q21.33-q31.1 which unmasked the frameshift mutation were identified in the proband. Despite the large de novo deletion, which can be classified as a pathogenic copy number variant (CNV), the patient’s clinical presentation is mostly consistent with that of CLN5, except for early developmental delay which is believed due to the large deletion. Both variants were detected simultaneously by exome sequencing.ConclusionsThis is the first report of whole gene deletion in combination with a novel pathogenic sequence variant in a CLN5 patient. The two mutations detected with whole exome sequencing simultaneously proved the advantage of the sequencing technology for genetic diagnostics.

Neuronal ceroid lipofuscinosis type 2: an Australian case series.

AimLate infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare neurodegenerative disorder presenting in children aged 2–4 years with seizures and loss of motor and language skills, followed by blindness and death in late childhood. Initial presenting features are similar to a range of common epilepsies. We aim to highlight typical clinical and radiological features that may prompt diagnosis of CLN2 disease in early disease stages.MethodsWe present a series of 13 Australian patients with CLN2 disease, describing clinical features, disease evolution, neuroimaging, electroencephalogram, biochemical and genetic results. Expert neuroradiological magnetic resonance imaging (MRI) analysis was retrospectively performed on 10 cases.ResultsTwelve patients presented with seizures, with initial seizures being focal (n = 4), generalised tonic–clonic (n = 3), absence (n = 3) and febrile (n = 2). Eleven patients (85%) had a language delay before the onset of seizures. Cerebellar or cerebral atrophy was noted in all patients on centralised MRI review, with abnormalities of the brain‐stem, ventricles, corpus callosum and hippocampi.ConclusionsEarly language delay with the onset of seizures at 2–4 years of age is the hallmark of CLN2 disease. MRI findings of early subtle atrophy in the cerebellum or posterior cortical regions should hasten testing for CLN2 disease to enable early initiation of enzyme replacement therapy.

Changing Times for CLN2 Disease: The Era of Enzyme Replacement Therapy.

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a progressive neurodegenerative disease that results in early-onset, severe, progressive, neurological disabilities, leading to death in late childhood or early adolescence. Management has relied on symptomatic care, and supportive and palliative strategies, but the approval of the enzyme replacement therapy cerliponase alfa in the USA and Europe in 2017 brought different treatment opportunities. We describe the natural history of CLN2 disease, its diagnosis and management, and the preclinical and clinical development of cerliponase alfa. A PubMed search was undertaken for cerliponase alfa and rhTPP1 to identify preclinical and clinical studies. The hallmark-presenting symptoms of CLN2 disease are unprovoked seizures and a history of language delay, and progression involves motor dysfunction, and cognitive and visual decline. Cerliponase alfa has shown efficacy and tolerability in mouse and canine models of CLN2 disease when delivered intracerebroventricularly. Administration of cerliponase alfa in patients with CLN2 disease has led to significant reductions in the rate of decline of motor and language functions in comparison with a natural history population. The approval of cerliponase alfa has brought a new era for CLN2 disease, highlighting the need to understand different patterns of disease progression and clinical needs in treated patients.

Results of a family survey on healthcare resource needs in children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease in the US and Canada

Results of a family survey on healthcare resource needs in children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease in the US and Canada

Cerliponase alfa for the treatment of atypical phenotypes of CLN2 disease: A retrospective case series

Background:The classic phenotype of CLN2 disease (neuronal ceroid lipofuscinosis type 2) typically manifests between ages 2 and 4 years with a predictable clinical course marked by epilepsy, langua...

Current understanding of language development in late infantile neuronal ceroid lipofuscinosis type 2 (CLN2 disease)

Current understanding of language development in late infantile neuronal ceroid lipofuscinosis type 2 (CLN2 disease)

Atypical neuronal ceroid lipofuscinosis type 2 (CLN2 disease): A case report

Ocular manifestations are observed in 25% of patients with Takayasu's arteritis. Its signs and symptoms can be very variable. The case is presented of a 41-year-old woman with progressive vision loss in her right eye secondary to ischaemic retinal arterial occlusion. After a systematic study, a PPD skin test compatible with tuberculosis was found to be the only alteration. After ruling out other causes, and based on the initial suspicion of tuberculous retinal vasculitis, treatment was started with antimicrobial agents and systemic corticosteroids, without any therapeutic response. Eighteen months later, the patient developed acute kidney failure, secondary to right renal artery stenosis. The CT-angiography revealed a thickening of the aortic arch and its branches, and Takayasuś arteritis was finally diagnosed. Therefore, emphasis is made on the importance of the ophthalmologist in the diagnosis of Takayasuś arteritis, in which its ophthalmological manifestations can be an early sign of the disease.El 25% de los pacientes con arteritis de Takayasu presentan manifestaciones oculares siendo el modo de presentación variable. Presentamos una mujer de 41 años de edad con pérdida progresiva de la visión en un ojo secundaria a una oclusión arterial retiniana isquémica. Habiendo descartado otras causas y con PPD sospechosa de tuberculosis, se consideró diagnóstico presuntivo TBC. Se inició tratamiento anti-infeccioso y anti-inflamatorio sistémico, sin respuesta terapéutica. A los 18 meses, se produjo un fallo renal agudo secundario a la estenosis de la arteria renal derecha. El angio-TC reveló un engrosamiento del arco aórtico y de sus ramas, diagnosticándose finalmente arteritis de Takayasu. Por lo tanto, se enfatiza la importancia del médico oftalmólogo en el diagnóstico de la enfermedad cuya manifestación oftalmológica potencialmente asociada, se puede presentar de forma inicial y tempranamente.

Family survey results of 7 children with atypical neuronal ceroid lipofuscinosis type 2 (CLN2) disease in the United States

Dyslipidemia is one of the main risk factors in cardiovascular disease in patients with diabetes mellitus type 2 (DM2). The aim of this study is to evaluate the prevalence and risk factors associated with dyslipidemia in the population with diabetes mellitus type 2 in the region of Cantabria.This is a transversal study carried out at Cantabrian primary health care centers (n = 680). A representative, random sample of the population with DM2, ranging from 18 to 85, was selected using a multistage procedure. The medical records were obtained, and by means of interviews the data of the risk factors to be studied was secured. The correlation with dyslipidemia was analyzed by means of logistic regression.There were 52.1% of males, the average age was 69.8, the evolution of diabetes was 9.99 years, 84.3% had arterial hypertension, 76.6% were overweight or obese and the average HbA1c was 6.96%. The prevalence of dyslipidemia was 85.3%, and in the bivariate analysis this is associated with a history of peripheral artery disease, controlled diabetes, antihypertensive treatment, glomerular filtration, HbA1c >7%, body fat estimated as being either overweight or obese, a history of cardiovascular disease, age and HbA1c.In the multivariate analysis the independent factors were being female and a history of cardiovascular disease.The prevalence of dyslipidemia in our study was 85.3%, and is consistent with figures found in previous published studies. The independent associated risk factors were being female and a past medical history of cardiovascular disease.La dislipidemia es uno de los principales factores de riesgo de enfermedad cardiovascular en pacientes con diabetes mellitus tipo 2 (DM2). El objetivo de este estudio es evaluar la prevalencia y factores de riesgo asociados a la dislipidemia en la población con DM2 de la Comunidad de Cantabria.Es un estudio transversal realizado en centros de Atención Primaria del Servicio Cántabro de Salud (n = 680). Se seleccionó una muestra aleatorizada representativa de la población con DM2 de 18 a 85 años mediante un procedimiento polietápico. Se obtuvieron de la historia clínica y mediante entrevista los datos de los factores de riesgo a estudio. Se analizó la asociación con la dislipidemia mediante regresión logística.El 52,1% eran hombres, la edad media fue de 69,8 años, la evolución de la diabetes de 9,99 años, el 84,3% tenían HTA, el 76,6% sobrepeso/obesidad y la HbA1c media era de 6,96%. La prevalencia de dislipidemia fue del 85,3% y en el análisis bivariado se asoció con antecedente de enfermedad vascular periférica, diabetes controlada, tratamiento antihipertensivo, filtrado glomerular, HbA1c > 7%, grasa corporal estimada en sobrepeso y obesidad, antecedente de enfermedad cardiovascular, edad y HbA1c.En el análisis multivariante los factores independientes fueron el sexo femenino y el antecedente de enfermedad cardiovascular.La prevalencia de dislipidemia en nuestro estudio fue del 85,3% y es consistente con la encontrada en estudios previos publicados. Los factores de riesgo asociados de forma independiente fueron el sexo femenino y el antecedente personal de enfermedad cardiovascular.

The Challenges of Living with and Caring for a Child or Children Affected by Neuronal Ceroid Lipofuscinosis Type 2 Disease: In-Depth Family Surveys in the United Kingdom and Germany

Limited research has investigated the challenges faced by families caring for children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease. Face-to-face, mixed-method, in-depth surveys were conducted with 19 families (23 children) in the UK (n=9) and Germany (n=10) to assess the impact of caring for children with CLN2 disease, using national wellbeing and quality of life (QoL) measures. Primary (n=19) and secondary (n=10) caregivers, adult siblings (n=2), and child siblings (n=2) were included. Caregivers reported reduced health-related QoL compared with age and gender-matched controls (mean utility scores 0.08 and 0.11 lower in Germany and the UK, respectively). Hours of caregiving were significantly higher relative to that provided to a child of normal health, with stress, back pain, and reductions in sleep being recorded. Lower life satisfaction and happiness with partners were also reported, along with significant financial burden. Those caring for children in the late stage of disease were more greatly impacted than those with children in the rapidly progressive stage, or who were bereaved. The results of this study make clear the importance of emotional and practical support for caregivers and siblings coping with CLN2 disease.

Neuronal ceroid lipofuscinoses type 8: Expanding genotype/phenotype diversity-first report from Saudi Arabia

Neuronal ceroid lipofuscinoses (NCLs) are the most common group of neurodegenerative diseases that presents in childhood and are characterized by seizures and progressive neurological deterioration, which results in dementia, ataxia, visual failure, and various forms of abnormal movement. The most common form of neuronal ceroid lipofuscinoses is late infantile (LI-NCL), in association with the genes CLN2, CLN5, CLN6, and CLN8. We report the cases of neuronal ceroid lipofuscinoses type 8 in 3 patients from 2 unrelated families, which was confirmed by molecular testing in 2 of them. Multiple spontaneous abortions, early death, and early onset of motor disability were observed in our cases, reflecting a possible association of NCL 8 with other unrecognized neurodegenerative diseases. Our results expand the genotypic/phenotypic background of variant late Infantile-NCL in Arabic ethnicity.

Review of Cerliponase Alfa: Recombinant Human Enzyme Replacement Therapy for Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2.

The objective of this review is to summarize the pharmacology, efficacy, and safety of cerliponase alfa for the treatment of late infantile neuronal ceroid lipofuscinosis type 2 (CLN2). Cerliponase alfa is recombinant human tripeptidyl peptidase 1 enzyme replacement therapy. A phase 1/2 trial established the efficacy and safety of cerliponase alfa for treatment of neuronal ceroid lipofuscinosis type 2. Treatment with intracerebroventricular cerliponase alfa resulted in slower decline of motor and language functions compared with natural history controls. Common adverse events include convulsions, electrocardiography abnormalities, pyrexia, vomiting, and upper respiratory tract infections. Intracerebroventricular device-related adverse events also occur. Cerliponase alfa is the first therapy for neuronal ceroid lipofuscinosis type 2 that targets the disease etiology. Cerliponase alfa is effective in delaying the progression of motor language decline for patients with neuronal ceroid lipofuscinosis type 2.

Mice deficient in the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1) display a complex retinal phenotype

Neuronal ceroid lipofuscinosis (NCL) type 1 (CLN1) is a neurodegenerative storage disorder caused by mutations in the gene encoding the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). CLN1 patients suffer from brain atrophy, mental and motor retardation, seizures, and retinal degeneration ultimately resulting in blindness. Here, we performed an in-depth analysis of the retinal phenotype of a PPT1-deficient mouse, an animal model of this condition. Reactive astrogliosis and microgliosis were evident in mutant retinas prior to the onset of retinal cell loss. Progressive accumulation of storage material, a pronounced dysregulation of various lysosomal proteins, and accumulation of sequestosome/p62-positive aggregates in the inner nuclear layer also preceded retinal degeneration. At advanced stages of the disease, the mutant retina was characterized by a significant loss of ganglion cells, rod and cone photoreceptor cells, and rod and cone bipolar cells. Results demonstrate that PPT1 dysfunction results in early-onset pathological alterations in the mutant retina, followed by a progressive degeneration of various retinal cell types at relatively late stages of the disease. Data will serve as a reference for future work aimed at developing therapeutic strategies for the treatment of retinal degeneration in CLN1 disease.

Paediatric-onset neuronal ceroid lipofuscinosis: first symptoms and presentation at diagnosis.

Neuronal ceroid lipofuscinoses (NCLs) are rare, progressive disorders. Through this series of 20 patients with NCL, we illustrate differences between subtypes in their presenting symptoms and clinical, imaging, and electrophysiological results to raise awareness of symptom diversity. Data were available on presenting symptoms, genetics, magnetic resonance imaging (MRI), electroencephalography (including with low-frequency intermittent photic stimulation), visual responses, and electron microscopy. Causal mutations were identified in 10 patients. Eleven patients had neuronal ceroid lipofuscinosis type 2 (CLN2) disease and their most common presenting symptom was seizures, although motor and language defects were also reported. Five patients with CLN2 disease showed abnormalities at initial MRI, but only three showed a photic response with low-frequency stimulation. Seizures were not as common a presenting symptom in other NCL subtypes. Patients with NCLs present with diverse symptoms, which may not be characteristic in early disease stages. These signs and symptoms should lead to rapid diagnostic confirmatory testing for NCLs. WHAT THIS PAPER ADDS: Disease presentation is not uniform for neuronal ceroid lipofuscinoses. Characteristic clinical test results may not be identified in early disease stages.

Genetic and phenotypic features of patients with childhood ataxias diagnosed by next-generation sequencing gene panel

BackgroundThe purpose of this prospective study was to identify the characteristics of pediatric recessive ataxias and the mutations leading to them. MethodsEighty-four pediatric patients aged 0–18 years presenting to our clinic, evaluated by means of imaging, metabolic or pathological investigation, or single-gene test, in whom Friedreich’s ataxia was excluded, and predicted to carry the progressive autosomal recessive ataxia gene were included in the study. Patients’ demographic, clinical, laboratory, and radiological characteristics were recorded. DNA and panel sequencing directed toward ataxia-related genes was performed using the next-generation sequencing method. ResultsA molecular diagnosis was established in 21 (25%) of the 84 patients. Genetically, infantile neuroaxonal dystrophy (7/21), ataxia with oculomotor apraxia type 1 (5/21), neuronal ceroid lipofuscinosis type 5 (2/21), ataxia with oculomotor apraxia type 2 (1/21), Lafora disease (1/21), tremor ataxia syndrome accompanying central hypomyelination (1/21), Charlevoix-Saguenay ataxia (1/21), Marinesco-Sjögren syndrome (1/21), VLDRL-associated cerebellar hypoplasia (1/21), and TSEN54-related pontocerebellar hypoplasia (1/21) mutations were detected. ConclusionsApproximately 25% of our patients were diagnosed. Novel mutations in the known genes were identified and are important in terms of phenotype-genotype correlation.

Clinical Application of Targeted Next-Generation Sequencing Panels and Whole Exome Sequencing in Childhood Epilepsy

Genetic diagnosis of childhood epilepsy is crucial to provide disease-specific treatments. This report describes the genetic landscape of childhood epilepsy revealed by targeted next-generation sequencing panels for epilepsy (TNGSP-E) and whole exome sequencing (WES). In this retrospective cohort study, TNGSP-E and/or WES were applied to identify underlying genetic diagnoses in children seen in a single Pediatric Epilepsy Genetics Clinic. We reviewed electronic patient charts for phenotypes and biochemical, genetic, and neuroimaging investigations. Forty-four different genetic diagnoses were confirmed in 71 of 197 patients (36%; 95% CI 29.3%–43.2%). The diagnostic yield of WES (37%) was 1.9-fold greater than the diagnostic yield of TNGSP-E (19.0%; P=.0018). The number of genes included in TNGSP-E was not correlated with whether or not the test resulted in a diagnosis (Pearson's R=-0.02, P=.8). Inherited metabolic disorders accounted for 13% of the genetic diagnoses, despite abnormal metabolic investigations being an exclusion criteria. There was a direct treatment implication in 6% of patients with inherited metabolic disorders including pyridoxine dependent epilepsy, glucose transporter 1 deficiency and neuronal ceroid lipofuscinosis type 2. Additionally, there might be some treatment implications in 30% of patients with genetic diagnoses including SCN1A, SCN2A, SCN8A, and KCNQ2 associated epilepsies by application of effective anti-epileptic drugs or the ketogenic diet therapy. The high diagnostic yield of clinical molecular genetic investigations and their disease-specific treatment implications highlight the importance of genetic diagnosis in childhood epilepsy. We recommend a stepwise diagnostic algorithm including metabolic investigations for treatable disorders, chromosomal microarray analysis, TNGSP-E, and WES.

Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is an autosomal recessive condition caused by variants in the TPP1 gene, leading to deficient activity of the lysosomal enzyme tripeptidyl peptidase I (TPP1). We update on the spectrum of TPP1 variants associated with CLN2 disease, comprising 131 unique variants from 389 individuals (717 alleles) collected from the literature review, public databases, and laboratory communications. Previously unrecorded individuals were added to the UCL TPP1‐specific database. Two known pathogenic variants, c.509–1 G>C and c.622 C>T (p.(Arg208*)), collectively occur in 60% of affected individuals in the sample, and account for 50% of disease‐associated alleles. At least 86 variants (66%) are private to single families. Homozygosity occurs in 45% of individuals where both alleles are known (87% of reported individuals). Atypical CLN2 disease, TPP1 enzyme deficiency with disease onset and/or progression distinct from classic late‐infantile CLN2, represents 13% of individuals recorded with associated phenotype. NCBI ClinVar currently holds records for 37% of variants collected here. Effective CLN2 disease management requires early diagnosis; however, irreversible neurodegeneration occurs before a diagnosis is typically reached at age 5. Timely classification and public reporting of TPP1 variants is essential as molecular testing increases in use as a first‐line diagnostic test for pediatric‐onset neurological disease.

Modelling of Neuronal Ceroid Lipofuscinosis Type 2 in Dictyostelium discoideum Suggests That Cytopathological Outcomes Result from Altered TOR Signalling.

The neuronal ceroid lipofuscinoses comprise a group of neurodegenerative disorders with similar clinical manifestations whose precise mechanisms of disease are presently unknown. We created multiple cell lines each with different levels of reduction of expression of the gene coding for the type 2 variant of the disease, Tripeptidyl peptidase (Tpp1), in the cellular slime mould Dictyostelium discoideum. Knocking down Tpp1 in Dictyostelium resulted in the accumulation of autofluorescent material, a characteristic trait of Batten disease. Phenotypic characterisation of the mutants revealed phenotypic deficiencies in growth and development, whilst endocytic uptake of nutrients was enhanced. Furthermore, the severity of the phenotypes correlated with the expression levels of Tpp1. We propose that the phenotypic defects are due to altered Target of Rapamycin (TOR) signalling. We show that treatment of wild type Dictyostelium cells with rapamycin (a specific TOR complex inhibitor) or antisense inhibition of expression of Rheb (Ras homologue enriched in the brain) (an upstream TOR complex activator) phenocopied the Tpp1 mutants. We also show that overexpression of Rheb rescued the defects caused by antisense inhibition of Tpp1. These results suggest that the TOR signalling pathway is responsible for the cytopathological outcomes in the Dictyostelium Tpp1 model of Batten disease.

Mutations in ATP13A2 (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in further phenotypic expansion

BackgroundAmyotrophic lateral sclerosis [1] is a genetically heterogeneous neurodegenerative disorder, characterized by late-onset degeneration of motor neurons leading to progressive limb and bulbar weakness, as well as of the respiratory muscles, which is the primary cause of disease fatality. To date, over 25 genes have been implicated as causative in ALS with C9orf72, SOD1, FUS, and TARDBP accounting for the majority of genetically positive cases.ResultsWe identified two patients of Italian and French ancestry with a clinical diagnosis of juvenile-onset ALS who were mutation-negative in any of the known ALS causative genes. Starting with the index case, a consanguineous family of Italian origin, we performed whole-exome sequencing and identified candidate pathogenic mutations in 35 genes, 27 of which were homozygous. We next parsed all candidates against a cohort of 3641 ALS cases; only ATP13A2 was found to harbor recessive changes, in a patient with juvenile-onset ALS, similar to the index case. In vivo complementation of ATP13A2 using a zebrafish surrogate model that focused on the assessment of motor neuron morphology and cerebellar integrity confirmed the role of this gene in central and peripheral nervous system maintenance and corroborated the damaging direction of effect of the change detected in the index case of this study.ConclusionsWe here expand the phenotypic spectrum associated with genetic variants in ATP13A2 that previously comprised Kufor-Rakeb syndrome, spastic paraplegia 78, and neuronal ceroid lipofuscinosis type 12 (CLN12), to also include juvenile-onset ALS, as supported by both genetic and functional data. Our findings highlight the importance of establishing a complete genetic profile towards obtaining an accurate clinical diagnosis.