Adolescent-Onset and Adult-Onset Vitamin-Responsive Neurogenetic Diseases: A Review.

Importance: Vitamin-responsive inherited diseases are among the rare genetic disorders with a specific pharmacological treatment. Many of these conditions have a prominent neurological phenotype that is mainly reported in children. Being rare and often strikingly different in adult-onset forms, they are still poorly known in the medical fields specific to adults. Observation: This article reviews all articles reporting cases of patients with a genetically confirmed inherited vitamin-responsive neurological disease and neurological onset after the age of 10 years. On this basis, 24 different diseases are described, involving vitamins A, B1, B2, B3, B6, B8, B9, B12, E, and tetrahydrobiopterin (BH4). Information such as clinical symptoms, disease course, imaging studies, biochemical alterations, and response to treatment present an overall picture of these patients. Conclusions and Relevance: Vitamin-responsive neurogenetic diseases represent a group of rare conditions that are probably underdiagnosed in adults and may have a dramatic response to treatment when started early in the course of the disease. In this review, main features of the adult-onset forms are defined and simple key messages are provided to help identify clinical situations when specific diagnostic tests should be performed and/or vitamins should be promptly administered.

High diagnostic value of plasma Niemann-Pick type C biomarkers in adults with selected neurological and/or psychiatric disorders.

Late-onset Niemann-Pick type C (NP-C) is a rare, underdiagnosed lysosomal disease with neurological manifestations. A specific treatment, miglustat, can stabilize the disease if given early. Recently, three plasma screening biomarkers (PSBs) were developed [cholestane3ß,5α,6ßtriol (C-triol), 7-ketocholesterol (7-KC), and lysosphingomyelin-509 (LSM-509)], allowing a simpler and quite robust screening of patients suitable for genetic testing. The objective of our study was to evaluate practical utility and feasibility of large-scale PSB screening for NP-C in selected adult patients. Patients were prospectively enrolled if they showed, starting from 12 years of age, at least one of the three initial neuro-psychiatric manifestations described in NP-C: (1) gait disorder (cerebellar and/or dystonic); (2) cognitive decline with frontal lobe syndrome; (3) atypical psychosis. PSBs were measured in plasma of all patients and, if positive (LSM-509 and/or C-triol + 7-KC elevated), sequencing of NPC1 and NPC2 genes was performed. A total of 251 patients [136 males, 115 females; median age 42.1 (range 12.2-85.6) years] were screened. Six patients had positive PSBs. Two were confirmed to have NP-C (0.8% diagnostic yield, both with all three PSBs highly increased, especially LSM-509). False-positive rate was 1.2%, which was identical if only considering LSM-509. By contrast, false-positive rates were 8.1% and 5.7% for 7-KC and C-triol, respectively. We showed that selecting patients with neurologic and/or psychiatric symptoms consistent with NP-C for large-scale PSB screening is a simple and valid strategy to identify new adult NP-C patients, and would probably lead to earlier diagnosis and treatment administration if widely applied.

Home monitoring of maintenance intravenous immunoglobulin therapy in patients with chronic inflammatory neuropathy.

To evaluate the utility of different outcome measures to monitor dose adjustment of intravenous immunoglobulin (IVIg) therapy in patients with chronic inflammatory neuropathy (CIN). We assessed the adjustment of IVIg maintenance therapy in 20 patients (10 CIDP and 10 MMN) by regularly monitoring grip strength (GS) using a Martin Vigorimeter, RODS, and quality of life using the SF-36 questionnaire. These measures were regularly performed by the patient at home. We also assessed the extended MRC sumscore (eMRC sumscore) at each outpatient visit for IVIg infusion. We also enrolled 30 healthy controls to measure any possible training effect of GS with time and to analyze random fluctuation of GS. Clinically relevant change was detected by eMRC sumscore in 14 (93%) patients, by RODS in 11 (73%) patients, and by GS in 8 (53%) patients. Early sensitivity was greatest for RODS (73%), followed by GS (53%), and eMRC sumscore (27%). This differed from CIDP, with an early change in RODS in 100% of patients, and MMN with an early change in GS in 75%. None of the outcome measures alone was sufficient to detect clinically significant changes in all patients. Home monitoring of outcome measures objectively assisted clinical decision during individualization of IVIg treatment. We recommend a multimodal approach using different outcome measures to monitor the individual patient with CIN.

Natural History of Adult Patients with GM2 Gangliosidosis.

OBJECTIVE: GM2 gangliosidoses are lysosomal diseases due to biallelic mutations in the HEXA (Tay-Sachs disease [TS]) or HEXB (Sandhoff disease [SD]) genes, with subsequent low hexosaminidase(s) activity. Most patients have childhood onset, but some experience the first symptoms during adolescence/adulthood. This study aims to clarify the natural history of adult patients with GM2 gangliosidosis. METHODS: We retrospectively described 12 patients from a French cohort and 45 patients from the literature. RESULTS: We observed 4 typical presentations: (1) lower motoneuron disorder responsible for proximal lower limb weakness that subsequently expanded to the upper limbs, (2) cerebellar ataxia, (3) psychosis and/or severe mood disorder (only in the TS patients), and (4) a complex phenotype mixing the above 3 manifestations. The psoas was the first and most affected muscle in the lower limbs, whereas the triceps and interosseous were predominantly involved in the upper limbs. A longitudinal study of compound motor action potentials showed a progressive decrease in all nerves, with different kinetics. Sensory potentials were sometimes abnormally low, mainly in the SD patients. The main brain magnetic resonance imaging feature was cerebellar atrophy, even in patients without cerebellar symptoms. The prognosis was mainly related to gait disorder, as we showed that beyond 20 years of disease evolution, half of the patients were wheelchair users. INTERPRETATION: Improved knowledge of GM2 gangliosidosis in adults will help clinicians achieve correct diagnoses and better inform patients on the evolution and prognosis. It may also contribute to defining proper outcome measures when testing emerging therapies. ANN NEUROL 2020;87:609-617.

Cholic acid as a treatment for cerebrotendinous xanthomatosis in adults.

Cerebrotendineous xanthomatosis (CTX) is an autosomal recessive disorder of bile acids synthesis. Patients may present with a variety of clinical manifestations: bilateral cataract and chronic diarrhea during childhood, then occurrence of neurological debilitating symptoms in adulthood (cognitive decline, motor disorders). Plasma cholestanol is used as a diagnostic marker of CTX, and to monitor the response to the treatment. Current treatment for CTX is chenodeoxycholic acid (CDCA), which was reported to improve and/or stabilize clinical status and decrease levels of plasma cholestanol. Rare published reports have also suggested a potential efficacy of cholic acid (CA) in patients with CTX. In this retrospective Franco-Belgian multicentric study, we collected data from 12 patients treated with CA, evaluating their clinical status, cholestanol levels and adverse effects during the treatment period. The population was divided in two subgroups: treatment-naive (who never had CDCA prior to CA) and non-treatment-naive patients (who had CDCA prior to CA introduction). We found that treatment with CA significantly and strongly reduced cholestanol levels in all patients. Additionally, 10 out of 12 patients clinically improved or stabilized with CA treatment. Worsening was noted in one treatment-naïve patient and one non-treatment-naïve patient, but both patients experienced similar outcomes with CDCA treatment as well. No adverse effects were reported from patients with CA treatment, whereas elevated transaminases were observed in some patients while they were treated with CDCA. In conclusion, these findings suggest that CA may be a suitable alternative treatment for CTX, especially in patients with side effects related to CDCA.

Paradoxical Effect of Levetiracetam in Newly Diagnosed Type II Focal Cortical Dysplasia.

A paradoxical effect of antiepileptic drugs was defined as an increased seizure frequency or severity occurring shortly after introducing a drug considered effective for that kind of epilepsy. In addition, this effect should occur at nontoxic drug serum levels. So far, pathophysiological mechanisms underlying this phenomenon have not been clarified. Recent evidence suggests that the variability of drug effects may depend on precise intrinsic properties of dynamic networks involving the drug and its binding site. Although several reports of paradoxical seizure exacerbation have been reported for levetiracetam (LEV), a possible association with focal cortical dysplasia has never been described nor investigated. In this report, we document a paradoxical effect induced by LEV monotherapy in a patient with type II focal cortical dysplasia at LEV serum levels within the therapeutic range. A hint of pathophysiological hypothesis underlying this potential relationship will be also suggested.

Environmental factors and multiple sclerosis severity: a descriptive study.

Growing evidence suggests that environmental factors play a key role in the onset of multiple sclerosis (MS). This study was conducted to examine whether environmental factors may also be associated with the evolution of the disease. We collected data on smoking habits, sunlight exposure and diet (particularly consumption of vitamin D-rich foods) from a sample of 131 MS patients. We also measured their serum vitamin D concentration. The clinical impact of MS was quantified using the Multiple Sclerosis Severity Score (MSSS); MS was considered "severe" in patients with MSSS ≥ 6, and "mild" in patients with MSSS ≤ 1. The results showed a strong association between serum vitamin D concentration and both sunlight exposure (26.4 ± 11.9 ng/mL vs. 16.5 ± 12.1 ng/mL, p = 0.0004) and a fish-rich diet (23.5 ± 12.1 ng/mL vs. 16.1 ± 12.4 ng/mL, p = 0.005). Patients reporting frequent sunlight exposure had a lower MSSS (2.6 ± 2.4 h vs. 4.6 ± 2.6 h, p < 0.001). The mild MS patients reported much more frequent sunlight exposure (75% mild MS vs. 25% severe MS p = 0.004, Chi square test). A higher serum vitamin D concentration determined a lower risk of developing severe MS, adjusted for sunlight exposure (OR = 0.92 for one unit increase in vitamin D, 95% CI: 0.86-0.97, p = 0.005). A stronger inverse association emerged between frequent sunlight exposure and the risk of severe MS (OR = 0.26, 95% CI: 0.09-0.71, p = 0.009). Our data show that an appropriate diet and adequate expose to sunlight are associated with less aggressive MS.