The collective burden of childhood dementia: a scoping review.

Childhood dementia is a devastating and under-recognized group of disorders with a high level of unmet need. Typically monogenic in origin, this collective of individual neurodegenerative conditions are defined by a progressive impairment of neurocognitive function, presenting in childhood and adolescence. This scoping review aims to clarify definitions and conceptual boundaries of childhood dementia and quantify the collective disease burden. A literature review identified conditions that met the case definition. An expert clinical working group reviewed and ratified inclusion. Epidemiological data were extracted from published literature and collective burden modelled. One hundred and seventy genetic childhood dementia disorders were identified. Of these, 25 were analysed separately as treatable conditions. Collectively, currently untreatable childhood dementia was estimated to have an incidence of 34.5 per 100 000 (1 in 2900 births), median life expectancy of 9 years and prevalence of 5.3 per 100 000 persons. The estimated number of premature deaths per year is similar to childhood cancer (0-14 years) and approximately 70% of those deaths will be prior to adulthood. An additional 49.8 per 100 000 births are attributable to treatable conditions that would cause childhood dementia if not diagnosed early and stringently treated. A relational database of the childhood dementia disorders has been created and will be continually updated as new disorders are identified (https://knowledgebase.childhooddementia.org/). We present the first comprehensive overview of monogenic childhood dementia conditions and their collective epidemiology. Unifying these conditions, with consistent language and definitions, reinforces motivation to advance therapeutic development and health service supports for this significantly disadvantaged group of children and their families.

Sanfilippo syndrome: consensus guidelines for clinical care.

Sanfilippo syndrome is a group of rare, complex, and progressive neurodegenerative lysosomal storage disorders that is characterized by childhood dementia. The clinical management of patients with progressive neurological decline and multisystem involvement requires a multidisciplinary team with experience in the management of neurodegenerative disorders. Best practice guidelines for the clinical management of patients with these types of rare disorders are critical to ensure prompt diagnosis and initiation of appropriate care. However, there are no published standard global clinical care guidelines for patients with Sanfilippo syndrome. To address this, a literature review was conducted to evaluate the current evidence base and to identify evidence gaps. The findings were reviewed by an international steering committee composed of clinical experts with extensive experience in managing patients with Sanfilippo syndrome. The goal was to create a consensus set of basic clinical guidelines that will be accessible to and informed by clinicians globally, as well as providing a practical resource for families to share with their local care team who may not have experience with this rare disease. This review distills 178 guideline statements into an easily digestible document that provides evidence-based, expert-led recommendations for how to approach common management challenges and appropriate monitoring schedules in the care of patients with Sanfilippo syndrome.

Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder.

TIMMDC1 encodes the Translocase of Inner Mitochondrial Membrane Domain-Containing protein 1 (TIMMDC1) subunit of complex I of the electron transport chain responsible for ATP production. We studied a consanguineous family with two affected children, now deceased, who presented with failure to thrive in the early postnatal period, poor feeding, hypotonia, peripheral neuropathy and drug-resistant epilepsy. Genome sequencing data revealed a known, deep intronic pathogenic variant TIMMDC1 c.597-1340A>G, also present in gnomAD (~1/5000 frequency), that enhances aberrant splicing. Using RNA and protein analysis we show almost complete loss of TIMMDC1 protein and compromised mitochondrial complex I function. We have designed and applied two different splice-switching antisense oligonucleotides (SSO) to restore normal TIMMDC1 mRNA processing and protein levels in patients' cells. Quantitative proteomics and real-time metabolic analysis of mitochondrial function on patient fibroblasts treated with SSOs showed restoration of complex I subunit abundance and function. SSO-mediated therapy of this inevitably fatal TIMMDC1 neurologic disorder is an attractive possibility.

Patient care standards for primary mitochondrial disease in Australia: an Australian adaptation of the Mitochondrial Medicine Society recommendations.

This document provides consensus-based recommendations for general physicians and primary care physicians who diagnose and manage patients with mitochondrial diseases (MD). It builds on previous international guidelines, with particular emphasis on clinical management in the Australian setting. This statement was prepared by a working group of medical practitioners, nurses and allied health professionals with clinical expertise and experience in managing Australian patients with MD. As new treatments and management plans emerge, these consensus-based recommendations will continue to evolve, but current standards of care are summarised in this document.

Novel hyperkinetic dystonia-like manifestation and neurological disease course of Swedish Gaucher patients.

BACKGROUND: Neuronopathic Gaucher disease type 3 (GD3) is frequent in northern Sweden, whereas GD1 is found throughout the country. In a nation-wide study, we examined neurological manifestations and clinical course in 12 patients with GD3 and 13 patients with GD1. METHODS: The patients were evaluated by standardized neurological assessments. Every sixth month, the GD3 patients were rated with the modified Severity Scoring Tool. At baseline and at the 3years follow-up, patients underwent University of Pennsylvania Smell Identification Test, Montreal Cognitive Assessment and Hospital Anxiety and Depression Scale. When clinical signs were present, additional examinations were undertaken. RESULTS: Marked clinical heterogeneity was evident in both GD3 and GD1 groups. Several GD3 patients had a hitherto unreported rapid and repetitive dystonia-like hyperkinetic movement disorder. Most patients with GD3 have abnormalities of horizontal gaze, ataxia and focal epilepsy, some also had cognitive impairment, anxiety and hyposmia. Six GD3 patients, all homoallelic for L444P GBA1 mutations, have lived beyond 40years of age; and none has developed Parkinsonism. Two of the GD1 patients suffer from Parkinsonism; mild to complete hyposmia was present in six GD3 and five GD1 patients. Neither the group of GD3 nor GD1 patients had detectable progression of their neurological manifestations. CONCLUSIONS: These middle-aged and older Swedish GD3 or GD1 patients are clinically stable over time. However, we have identified unusual clinical features, discordant phenotypes and a hyperkinetic dystonia-like movement disorder which appears unique to this Swedish disease variant and expands the phenotype for GD.

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.

BACKGROUND: In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation. METHODS: We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion. RESULTS: A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications. CONCLUSIONS: Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).

Quantification of plasma sulfatides by mass spectrometry: Utility for metachromatic leukodystrophy.

Impaired sulfatide catabolism is the primary biochemical insult in patients with the inherited neurodegenerative disease, metachromatic leukodystrophy (MLD), and sulfatide elevation in body fluids is useful in the diagnostic setting. Here we used mass spectrometry to quantify fourteen species of sulfatide, in addition to the deacetylated derivative, lyso-sulfatide, using high pressure liquid chromatography-electrospray ionisation-tandem mass spectrometry in both positive and negative ion mode. A single phase extraction of 0.01 mL of MLD plasma identified all 14 sulfatide species in the positive ion mode but none in the negative ion mode. Interrogation of seven major and seven hydroxylated molecular species, as well as lyso-sulfatide, identified the C18 isoform as the most informative for MLD. The C18 produced a linear response and was below the limit of quantification (<10 pmol mL-1) in control plasma with concentrations in MLD plasma ranging from 12 to 196 pmol mL-1. Serial plasma samples from an MLD patient post-therapeutic bone marrow transplant proved similar to non-disease controls with C18 sulfatide concentrations below the limit of quantification, as did samples from three individuals with an arylsulfatase A pseudodeficiency - a population variant which appears deficient upon enzymatic assay, without manifestation of disease. These findings emphasise the utility of the C18 sulfatide species for the diagnosis of MLD and biochemical monitoring of MLD patients. Extension of this approach to a newborn screening card correctly identified an MLD patient at birth with elevated C18 sulfatide at levels almost double that present in the newborn card from his unaffected sibling, suggesting the methodology may have applicability for newborn screening.

Homozygous mutation of STXBP5L explains an autosomal recessive infantile-onset neurodegenerative disorder.

We report siblings of consanguineous parents with an infantile-onset neurodegenerative disorder manifesting a predominant sensorimotor axonal neuropathy, optic atrophy and cognitive deficit. We used homozygosity mapping to identify an ∼12-Mbp interval identical by descent (IBD) between the affected individuals on chromosome 3q13.13-21.1 with an LOD score of 2.31. We combined family-based whole-exome and whole-genome sequencing of parents and affected siblings and, after filtering of likely non-pathogenic variants, identified a unique missense variant in syntaxin-binding protein 5-like (STXBP5L c.3127G>A, p.Val1043Ile [CCDS43137.1]) in the IBD interval. Considering other modes of inheritance, we also found compound heterozygous variants in FMNL3 (c.114G>C, p.Phe38Leu and c.1372T>G, p.Ile458Leu [CCDS44874.1]) located on chromosome 12. STXBP5L (or Tomosyn-2) is expressed in the central and peripheral nervous system and is known to inhibit neurotransmitter release through inhibition of the formation of the SNARE complexes between synaptic vesicles and the plasma membrane. FMNL3 is expressed more widely and is a formin family protein that is involved in the regulation of cell morphology and cytoskeletal organization. The STXBP5L p.Val1043Ile variant enhanced inhibition of exocytosis in comparison with wild-type (WT) STXBP5L. Furthermore, WT STXBP5L, but not variant STXBP5L, promoted axonal outgrowth in manipulated mouse primary hippocampal neurons. However, the FMNL3 p.Phe38Leu and p.Ile458Leu variants showed minimal effects in these cells. Collectively, our clinical, genetic and molecular data suggest that the IBD variant in STXBP5L is the likely cause of the disorder.

Collagen VI glycine mutations: perturbed assembly and a spectrum of clinical severity.

OBJECTIVE: The collagen VI muscular dystrophies, Bethlem myopathy and Ullrich congenital muscular dystrophy, form a continuum of clinical phenotypes. Glycine mutations in the triple helix have been identified in both Bethlem and Ullrich congenital muscular dystrophy, but it is not known why they cause these different phenotypes. METHODS: We studied eight new patients who presented with a spectrum of clinical severity, screened the three collagen VI messenger RNA for mutations, and examined collagen VI biosynthesis and the assembly pathway. RESULTS: All eight patients had heterozygous glycine mutations toward the N-terminal end of the triple helix. The mutations produced two assembly phenotypes. In the first patient group, collagen VI dimers accumulated in the cell but not the medium, microfibril formation in the medium was moderately reduced, and the amount of collagen VI in the extracellular matrix was not significantly altered. The second group had more severe assembly defects: some secreted collagen VI tetramers were not disulfide bonded, microfibril formation in the medium was severely compromised, and collagen VI in the extracellular matrix was reduced. INTERPRETATION: These data indicate that collagen VI glycine mutations impair the assembly pathway in different ways and disease severity correlates with the assembly abnormality. In mildly affected patients, normal amounts of collagen VI were deposited in the fibroblast matrix, whereas in patients with moderate-to-severe disability, assembly defects led to a reduced collagen VI fibroblast matrix. This study thus provides an explanation for how different glycine mutations produce a spectrum of clinical severity.