Hippocampal atrophy and white matter lesions characteristics can predict evolution to dementia in patients with vascular mild cognitive impairment.

Background: Vascular mild cognitive impairment (VMCI) is a transitional condition that may evolve into Vascular Dementia(VaD). Hippocampal volume (HV) is suggested as an early marker for VaD, the role of white matter lesions (WMLs) in neurodegeneration remains debated.

Objectives: Evaluate HV and WMLs as predictive markers of VaD in VMCI patients by assessing: (i)baseline differences in HV and WMLs between converters to VaD and non-converters, (ii) predictive power of HV and WMLs for VaD, (iii) associations between HV, WMLs, and cognitive decline, (iv)the role of WMLs on HV.

Anatomical Laser Microdissection of the Ileum Reveals mtDNA Depletion Recovery in A Mitochondrial Neuro-Gastrointestinal Encephalomyopathy (MNGIE) Patient Receiving Liver Transplant.

mitochondrial neuro-gastrointestinal encephalomyopathy (MNGIE) is a rare genetic disorder characterized by thymidine phosphorylase (TP) enzyme defect. The absence of TP activity induces the imbalance of mitochondrial nucleotide pool, leading to impaired mitochondrial DNA (mtDNA) replication and depletion. Since mtDNA is required to ensure oxidative phosphorylation, metabolically active tissues may not achieve sufficient energy production.

Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4: A Cross-sectional Study by the Italian DAISY Network.

Background And Objectives: Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability.

NGS in Hereditary Ataxia: When Rare Becomes Frequent.

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests.

Expert opinion on diagnosing, treating and managing patients with cerebrotendinous xanthomatosis (CTX): a modified Delphi study.

Background: Cerebrotendinous xanthomatosis (CTX) is a rare, chronic, progressive, neurodegenerative disorder requiring life-long care. Patients with CTX often experience a diagnostic delay. Although early diagnosis and treatment initiation can improve symptoms and prognosis, a standardised approach to diagnosis, treatment and management of patients is not yet established.

POLR3A variants in hereditary spastic paraparesis and ataxia: clinical, genetic, and neuroradiological findings in a cohort of Italian patients.

Mutations in POLR3A are characterized by high phenotypic heterogeneity, with manifestations ranging from severe childhood-onset hypomyelinating leukodystrophic syndromes to milder and later-onset gait disorders with central hypomyelination, with or without additional non-neurological signs. Recently, a milder phenotype consisting of late-onset spastic ataxia without hypomyelinating leukodystrophy has been suggested to be specific to the intronic c.1909 + 22G > A mutation in POLR3A.

Episodic ataxia and severe infantile phenotype in spinocerebellar ataxia type 14: expansion of the phenotype and novel mutations.

Introduction: Spinocerebellar ataxia type 14 (SCA14) is a dominantly inherited neurological disorder characterized by slowly progressive cerebellar ataxia. SCA14 is caused by mutations in PRKCG, a gene encoding protein kinase C gamma (PKCγ), a master regulator of Purkinje cells development.

Methods: We performed next-generation sequencing targeted resequencing panel encompassing 273 ataxia genes in 358 patients with genetically undiagnosed ataxia.

Challenges and resources in adult life with Joubert syndrome: issues from an international classification of functioning (ICF) perspective.

Background: Joubert Syndrome (JS) is a rare inherited neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation (i.e. the molar tooth sign) and variable organ involvement.

Longitudinal changes in MoCA performances in patients with mild cognitive impairment and small vessel disease. Results from the VMCI-Tuscany Study.

Objectives: The Montreal Cognitive Assessment (MoCA) is a cognitive screening test largely employed in vascular cognitive impairment, but there are no data about MoCA longitudinal changes in patients with cerebral small vessel disease (SVD). We aimed to describe changes in MoCA performance in patients with mild cognitive impairment (MCI) and SVD during a 2-year follow-up, and to evaluate their association with transition to major neurocognitive disorder (NCD).

Materials And Methods: Within the prospective observational VMCI-Tuscany Study, patients with MCI and SVD underwent a comprehensive clinical, neuropsychological, and functional evaluation at baseline, and after 1 and 2 years.

Evidence of enteric angiopathy and neuromuscular hypoxia in patients with mitochondrial neurogastrointestinal encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by thymidine phosphorylase (TP) enzyme defect. As gastrointestinal changes do not revert in patients undergone TP replacement therapy, one can postulate that other unexplored mechanisms contribute to MNGIE pathophysiology. Hence, we focused on the local TP angiogenic potential that has never been considered in MNGIE.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations.

Case Report: Early Treatment With Chenodeoxycholic Acid in Cerebrotendinous Xanthomatosis Presenting as Neonatal Cholestasis.

Cerebrotendinous xanthomatosis (CTX) is an inborn disorder of bile acid synthesis which causes progressive accumulation of toxic metabolites in various organs, particularly in brain and tendons. Most cases are diagnosed and treated in the second or third decade of life, when neurological involvement appears. We describe a case of CTX presenting as neonatal cholestasis.

Liver transplantation in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical long-term follow-up and pathogenic implications.

We report the longest follow-up of clinical and biochemical features of two previously reported adult mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients treated with liver transplantation (LT), adding information on a third, recently transplanted, patient. All three patients overcame the early post-operative period and tolerated immunosuppressive therapy. Plasma nucleoside levels dramatically decreased, with evidence of clinical improvement of ambulation and neuropathy.

Fibroblast growth factor 21 and grow differentiation factor 15 are sensitive biomarkers of mitochondrial diseases due to mitochondrial transfer-RNA mutations and mitochondrial DNA deletions.

Background: Diagnosis of mitochondrial diseases (MDs) is challenging, since they are multisystemic disorders, characterized by a heterogeneous symptomatology. Recently, an increase in serum levels of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) has been found in the majority of patients with MDs compared with healthy controls. On the other hand, the finding of low FGF21 and GDF15 levels in some patients with MDs suggests that different types of respiratory chain defects may lead to different profiles of these two proteins.

Multi-imaging study in a patient with cerebrotendinous xanthomatosis: radiology, clinic and pathology correlation of a rare condition.

Cerebrotendinous xanthomatosis (CTX) is a rare metabolic disease with autosomal recessive inheritance. It is caused by mutations of the CYP27A1 gene, which codifies for sterol 27-hydroxylase, an enzyme that is responsible for the synthesis of cholic acids. In CTX, cholic acid synthesis is impaired, leading to accumulation of the precursor chenodessossicholic acid) in various organs and tissues.

Eye movement changes in autosomal dominant spinocerebellar ataxias.

Oculomotor abnormalities are common findings in spinocerebellar ataxias (SCAs), a clinically heterogeneous group of neurodegenerative disorders with an autosomal dominant pattern of inheritance. Usually, cerebellar impairment accounts for most of the eye movement changes encountered; as the disease progresses, the involvement of extracerebellar structures typically seen in later stages may modify the oculomotor progression. However, ocular movement changes are rarely specific.

HTRA1 expression profile and activity on TGF-β signaling in HTRA1 mutation carriers.

High temperature requirement A1 (HTRA1) is a serine protease playing a modulatory role in various cell processes, particularly in the regulation of transforming growth factor-β (TGF-β) signaling. A deleterious role in late-onset cerebral small vessel diseases (CSVDs) of heterozygous HTRA1 mutations, otherwise causative in homozygosity of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, was recently suggested. However, the pathomechanism of these heterozygous mutations is still undefined.

The safety and effectiveness of chenodeoxycholic acid treatment in patients with cerebrotendinous xanthomatosis: two retrospective cohort studies.

Objective: To evaluate the safety and effectiveness of chenodeoxycholic acid (CDCA) treatment in patients with cerebrotendinous xanthomatosis (CTX).

Methods: Two retrospective cohort studies were conducted in CTX patients who underwent CDCA treatment: one in the Netherlands (NL; CDCA-STUK-15-001) and one in Italy (IT; CDCA-STRCH-CR-14-001). Eligible patients were aged 2-75 years, had been diagnosed with CTX, and were treated with CDCA orally for ≥1 year.

Nonsense mutations in alpha-II spectrin in three families with juvenile onset hereditary motor neuropathy.

Distal hereditary motor neuropathies are a rare subgroup of inherited peripheral neuropathies hallmarked by a length-dependent axonal degeneration of lower motor neurons without significant involvement of sensory neurons. We identified patients with heterozygous nonsense mutations in the αII-spectrin gene, SPTAN1, in three separate dominant hereditary motor neuropathy families via next-generation sequencing. Variable penetrance was noted for these mutations in two of three families, and phenotype severity differs greatly between patients.

Relevance of brain lesion location for cognition in vascular mild cognitive impairment.

Background: Vascular mild cognitive impairment (VMCI) is a potentially transitional state between normal aging and vascular dementia. The presence of macroscopic white matter lesions (WML) of moderate or severe extension on brain MRI is the hallmark of the VMCI.

Objective: To assess the clinical relevance of the frequency of WML in patients with VMCI independently of total lesion volume (LV).

Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study.

Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity-there are over 80 potential disease-associated genes-and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming.

Functional magnetic resonance imaging with encoding task in patients with mild cognitive impairment and different severity of leukoaraiosis.

Leukoaraiosis is one of the main contributors to mild cognitive impairment due to vascular damage (vascular MCI, VMCI), whose pathophysiology has not been fully elucidated yet. We aimed to shed light on such issue using functional MRI (fMRI). Sixteen patients with VMCI were enrolled and compared with twenty-five patients with MCI but without significant vascular damage (non-vascular MCI, NVMCI) and with fifteen healthy controls (HC).

RARE MUTATION IN A PATIENT WITH MYOTONIC DYSTROPHY TYPE 1 AND ADRENOCORTICOTROPIN HYPERRESPONSE TO CORTICOTROPIN-RELEASING HORMONE.

Objective: Myotonic dystrophy (DM) is a monogenic disorder. It is caused by expansion of a cytosine-thymineguanine triplet in the gene which encodes for myotonic dystrophy protein kinase (DMPK).

Methods: A 24-year-old man with DM and the mutation presented with elevated adrenocorticotropic hormone (ACTH) levels twice (152 and 185 pg/mL; normal value is 10 to 52 pg/mL) with normal cortisol levels (134.