An unusual diagnosis of alpha-mannosidosis with ocular anomalies: Behind the scenes of a hidden copy number variation.

Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder caused by biallelic mutations in the MAN2B1 gene and characterized by a wide clinical heterogeneity. Diagnosis for this multisystemic disorder is confirmed by the presence of either a deficiency in the lysosomal enzyme acid alpha-mannosidase or biallelic mutations in the MAN2B1 gene. This diagnosis confirmation is crucial for both clinical management and genetic counseling purposes. Here we describe a late diagnosis of alpha-mannosidosis in a patient presenting with syndromic intellectual disability, and a rare retinopathy, where reverse phenotyping played a pivotal role in interpreting the exome sequencing result. While a first missense variant was classified as a variant of uncertain significance, the phenotype-guided analysis helped us detect and interpret an in-trans apparent alu-element insertion, which appeared to be a copy number variant (CNV) not identified by the CNV caller. A biochemical analysis showing abnormal excretion of urinary mannosyloligosaccharide and an enzyme assay permitted the re-classification of the missense variant to likely pathogenic, establishing the diagnosis of alpha-mannosidosis. This work emphasizes the importance of reverse phenotyping in the context of exome sequencing.

Cognitive impairment in children and adults with cerebrotendinous xanthomatosis: A French cohort study.

Cerebrotendinous xanthomatosis is a rare and treatable metabolic disorder related to the accumulation of cholestanol. This disorder is primarily associated with motor and cognitive impairments, although the latter has not been extensively characterized. The objectives of this work were to define the cognitive profile found in cerebrotendinous xanthomatosis patients, investigate the progression of cognitive impairment over time, and search for radio-clinical correlations. Through a multicentric chart review study, we collected cognitive and radiological data from nine children and eighteen adults with genetically proven cerebrotendinous xanthomatosis. We performed a volumetric and morphological analysis of the brain magnetic resonance imaging. In our cohort, 44% (4/9) of children and 78% (14/18) of adults exhibited cognitive impairment that can be severe. The study revealed a significant impairment in various cognitive domains, specifically executive, attentional, language, and visuo-spatial. Among adults, 16% (3/18) developed dementia after age 50. These three patients had delayed chenodeoxycholic acid treatment and important cerebral atrophy. Besides these three cases of late-onset cognitive decline, Mini-Mental State Evaluation was generally stable, suggesting cognitive impairment due to a neurodevelopmental disorder and persisting in adulthood. Cognitive impairment was less common in children, possibly related to early chenodeoxycholic acid treatment in our cohort. The severity of magnetic resonance imaging abnormalities did not predict cognitive impairment in patients. Overall, in cerebrotendinous xanthomatosis, cognitive impairment can be severe and mainly neurodevelopmental. Early chenodeoxycholic acid treatment might be associated with a reduced risk of cognitive decline.

Plasma lysosphingolipids in GRN-related diseases: Monitoring lysosomal dysfunction to track disease progression.

GRN mutations are among the main genetic causes of frontotemporal dementia (FTD). Considering the progranulin involvement in lysosomal homeostasis, we aimed to evaluate if plasma lysosphingolipids (lysoSPL) are increased in GRN mutation carriers, and whether they might represent relevant fluid-based biomarkers in GRN-related diseases. We analyzed four lysoSPL levels in plasmas of 131 GRN carriers and 142 non-carriers, including healthy controls and patients with frontotemporal dementias (FTD) carrying a C9orf72 expansion or without any mutation. GRN carriers consisted of 102 heterozygous FTD patients (FTD-GRN), three homozygous patients with neuronal ceroid lipofuscinosis-11 (CLN-11) and 26 presymptomatic carriers (PS-GRN), the latter with longitudinal assessments. Glucosylsphingosin d18:1 (LGL1), lysosphingomyelins d18:1 and isoform 509 (LSM18:1, LSM509) and lysoglobotriaosylceramide (LGB3) were measured by electrospray ionization-tandem mass spectrometry coupled to ultraperformance liquid chromatography. Levels of LGL1, LSM18:1 and LSM509 were increased in GRN carriers compared to non-carriers (p < 0.0001). No lysoSPL increases were detected in FTD patients without GRN mutations. LGL1 and LSM18:1 progressively increased with age at sampling, and LGL1 with disease duration, in FTD-GRN. Among PS-GRN carriers, LSM18:1 and LGL1 significantly increased over 3.4-year follow-up. LGL1 levels were associated with increasing neurofilaments in presymptomatic carriers. This study evidences an age-dependent increase of ß-glucocerebrosidase and acid sphingomyelinase substrates in GRN patients, with progressive changes as early as the presymptomatic phase. Among FTD patients, plasma lysoSPL appear to be uniquely elevated in GRN carriers, and thus might serve as suitable non-invasive disease-tracking biomarkers of progression, specific to the pathophysiological process. Finally, this study might add lysoSPL to the portfolio of fluid-based biomarkers, and pave the way to disease-modifying approaches based on lysosomal function rescue in GRN diseases.

Plasma GM2 ganglioside potential biomarker for diagnosis, prognosis and disease monitoring of GM2-Gangliosidosis.

GM2-Gangliosidosis are a group of inherited lysosomal storage pathologies characterized by a large accumulation of GM2 ganglioside in the lysosome. They are caused by mutation in HEXA or HEXB causing reduced or absent activity of a lysosomal ß-hexosaminidase A, or mutation in GM2A causing defect in GM2 activator protein (GM2AP), an essential protein for the activity of the enzyme. Biochemical diagnosis relies on the measurement of ß-hexosaminidases A and B activities, which is able to detect lysosomal enzyme deficiency but fails to identify defects in GM2AP. We developed a rapid, specific and sensitive liquid chromatography-mass spectrometry-based method to measure simultaneously GM1, GM2, GM3 and GD3 molecular species. Gangliosides were analysed in plasma from 19 patients with GM2-Gangliosidosis: Tay-Sachs (n = 9), Sandhoff (n = 9) and AB variant of GM2-Gangliosidosis (n = 1) and compared to 20 age-matched controls. Among patients, 12 have a late adult-juvenile-onset and 7 have an infantile early-onset of the disease. Plasma GM2 molecular species were increased in all GM2-Gangliosidosis patients (19/19), including the patient with GM2A mutation, compared to control individuals and compared to patients with different other lysosomal storage diseases. GM234:1 and GM234:1/GM334:1 ratio discriminated patients from controls with 100% sensitivity and specificity. GM234:1 and GM234:1/GM334:1 were higher in patients with early-onset compared to those with late-onset of the disease, suggesting a relationship with severity. Longitudinal analysis in one adult with Tay-Sachs disease over 9 years showed a positive correlation of GM234:1 and GM234:1/GM334:1 ratio with age at sampling. We propose that plasma GM2 34:1 and its ratio to GM3 34:1 could be sensitive and specific biochemical diagnostic biomarkers for GM2-Gangliosidosis including AB variant and could be useful as a first line diagnostic test and potential biomarkers for monitoring upcoming therapeutic efficacy.

Diagnosis and management of hepatic encephalopathy: The French recommendations.

Hepatic encephalopathy (HE) is a frequent and severe complication of liver disease with poor patient outcomes. However, it is a poorly understood complication, with no consensus for diagnosis. Therefore, HE is often underdiagnosed. Differential diagnosis may be cumbersome because of non-specific symptoms, such as confusion, cognitive disorders, the aetiological factors of cirrhosis and comorbidities, which are often observed in cirrhotic patients. Therefore, an overt or covert form of HE should be systematically investigated. Advice is provided to drive patient work-up. Effective treatments are available to prevent or treat HE bouts, but the issue of single or combination therapy has not been resolved. Transjugular intrahepatic portosystemic shunt (TIPS) placement largely improved the prognosis of cirrhotic patients, but HE occurrence of HE is often a fear, even when post-TIPS HE can be avoided by a careful selection of patients and preventive treatment. HE is an indication of liver transplantation. However, its reversibility post-transplantation and the consequences of transplantation in patients with other causes of neurological disorders remain controversial, which supports the performance of an extensive work-up in expert centres for this subset of patients. The present guidelines assist clinicians in the diagnosis of the overt or covert form of HE to implement curative and preventive treatments and clarify which patients require referral to expert centres for consideration for liver transplantation. These guidelines are very clinically oriented and address different frequent clinical issues to help physicians make bedside decisions.

Mutation m.3395A > G in MT-ND1 leads to variable pathologic manifestations.

A non-synonymous mtDNA mutation, m.3395A > G, which changes tyrosine in position 30 to cysteine in p.MT-ND1, was found in several patients with a wide range of clinical phenotypes such as deafness, diabetes and cerebellar syndrome but no Leber's hereditary optic neuropathy. Although this mutation has already been described, its pathogenicity has not been demonstrated. Here, it was found isolated for the first time, allowing a study to investigate its pathogenicity. To do so, we constructed cybrid cell lines and carried out a functional study to assess the possible consequences of the mutation on mitochondrial bioenergetics. Results obtained demonstrated that this mutation causes an important dysfunction of the mitochondrial respiratory chain with a decrease in both activity and quantity of complex I due to a diminution of p.MT-ND1 quantity. However, no subcomplexes were found in cybrids carrying the mutation, indicating that the quality of the complex I assembly is not affected. Moreover, based on the crystal structure of p.MT-ND1 and the data found in the literature, we propose a hypothesis for the mechanism of the degradation of p.MT-ND1. Our study provides new insights into the pathophysiology of mitochondrial diseases and in particular of MT-ND1 mutations.

Diagnostic approach in adult-onset neurometabolic diseases.

Neurometabolic diseases are a group of individually rare but numerous and heterogeneous genetic diseases best known to paediatricians. The more recently reported adult forms may present with phenotypes strikingly different from paediatric ones and may mimic other more common neurological disorders in adults. Furthermore, unlike most neurogenetic diseases, many neurometabolic diseases are treatable, with both conservative and more recent innovative therapeutics. However, the phenotypical complexity of this group of diseases and the growing number of specialised biochemical tools account for a significant diagnostic delay and underdiagnosis. We reviewed all series and case reports of patients with a confirmed neurometabolic disease and a neurological onset after the age of 10 years, with a focus on the 36 treatable ones, and classified these diseases according to their most relevant clinical manifestations. The biochemical diagnostic approach of neurometabolic diseases lays on the use of numerous tests studying a set of metabolites, an enzymatic activity or the function of a given pathway; and therapeutic options aim to restore the enzyme activity or metabolic function, limit the accumulation of toxic substrates or substitute the deficient products. A quick diagnosis of a treatable neurometabolic disease can have a major impact on patients, leading to the stabilisation of the disease and cease of repeated diagnostic investigations, and allowing for familial screening. For the aforementioned, in addition to an exhaustive and clinically meaningful review of these diseases, we propose a simplified diagnostic approach for the neurologist with the aim to help determine when to suspect a neurometabolic disease and how to proceed in a rational manner. We also discuss the place of next-generation sequencing technologies in the diagnostic process, for which deep phenotyping of patients (both clinical and biochemical) is necessary for improving their diagnostic yield.

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.

Late-onset riboflavin transporter deficiency: a treatable mimic of various motor neuropathy aetiologies.

OBJECTIVE: Riboflavin transporter deficiencies (RTDs), involving SLC52A3 and SLC52A2 genes, have recently been related to Brown-Vialetto-Van Laere (BVVL) syndrome, a hereditary paediatric condition associating motor neuropathy (MN) and deafness. BVVL/RTD has rarely been reported in adult patients, but is probably underdiagnosed due to poor knowledge and lack of awareness of this form of disease among neurologists. In this study, we aimed to investigate the phenotype and prognosis of RTD patients with late-onset MN. METHODS: We retrospectively collected clinical, biological and electrophysiological data from all French RTD patients with MN onset after 10 years of age (n=6) and extracted data from 19 other similar RTD patients from the literature. RESULTS: Adult RTD patients with MN had heterogeneous clinical presentations, potentially mimicking amyotrophic lateral sclerosis or distal hereditary motor neuropathy (56%), multinevritis with cranial nerve involvement (16%), Guillain-Barré syndrome (8%) and mixed motor and sensory neuronopathy syndromes (20%, only in SLC52A2 patients). Deafness was often diagnosed before MN (in 44%), but in some patients, onset began only with MN (16%). The pattern of weakness varied widely, and the classic pontobulbar palsy described in BVVL was not constant. Biochemical tests were often normal. The majority of patients improved under riboflavin supplementation (86%). INTERPRETATION: Whereas late-onset RTD may mimic different acquired or genetic causes of motor neuropathies, it is a diagnosis not to be missed since high-dose riboflavin per oral supplementation is often highly efficient.

Long-term survival outcomes of patients with Niemann-Pick disease type C receiving miglustat treatment: A large retrospective observational study.

Miglustat has been indicated for the treatment of Niemann-Pick disease type C (NP-C) since 2009. The aim of this observational study was to assess the effect of miglustat on long-term survival of patients with NP-C. Data for 789 patients from five large national cohorts and from the NPC Registry were collected and combined. Miglustat-treated and untreated patients overall and within sub-groups according to age-at-neurological-onset, that is, early infantile-onset (<2 years), late infantile-onset (2 to <6 years), juvenile-onset (6 to <15 years), and adolescent/adult-onset (≥15 years) were analysed and compared. Survival was analysed from the time of first neurological manifestation (Neurological onset group, comprising 669 patients) and from diagnosis (Diagnosis group, comprising 590 patients) using a Cox proportional hazard model adjusted for various covariates. Overall, 384 (57.4%) patients in the Neurological onset group and 329 (55.8%) in the Diagnosis group were treated with miglustat. Miglustat treatment was associated with a significant reduction in risk of mortality in both groups (entire Neurological onset group, Hazard ratio [HR] = 0.51; entire Diagnosis group, HR = 0.44; both P < .001). The effect was observed consistently in all age-at-neurological-onset sub-groups (HRs = 0.3 to 0.7) and was statistically significant for late infantile-onset patients in both groups (Neurological onset group, HR = 0.36, P < .05; Diagnosis group, HR = 0.32, P < .01), and juvenile-onset patients in the Diagnosis group only (HR = 0.30, P < .05). Despite the limitations of the data that urge cautious interpretation, the findings are consistent with a beneficial effect of miglustat on survival in patients with NP-C.

Phosphoglycerate kinase deficiency: A nationwide multicenter retrospective study.

Phosphoglycerate kinase (PGK) deficiency is a rare X-linked metabolic disorder caused by mutations in the PGK1 gene. Patients usually develop various combinations of nonspherocytic hemolytic anemia (NSHA), myopathy, and central nervous system disorders. In this national multicenter observational retrospective study, we recorded all known French patients with PGK deficiency, and 3 unrelated patients were identified. Case 1 was a 32-year-old patient with severe chronic axonal sensorimotor polyneuropathy resembling Charcot-Marie-Tooth (CMT) disease, mental retardation, microcephaly, ophthalmoplegia, pes cavus, and the new c.323G > A PGK1 hemizygous mutation. Case 2 was a 71-year-old patient with recurrent exertional rhabdomyolysis, and a c.943G > A PGK1 hemizygous mutation. Case 3 was a 48-year-old patient with NSHA, retinitis pigmentosa, mental retardation, seizures, stroke, parkinsonism, and a c.491A > T PGK1 hemizygous mutation. This study confirms that PGK deficiency is an extremely rare disorder with a wide phenotypic spectrum, and demonstrates for the first time that PGK deficiency may affect the peripheral nervous system and present as a CMT-like disorder.

Development of a new tandem mass spectrometry method for urine and amniotic fluid screening of oligosaccharidoses.

RATIONALE: The first step in the diagnosis of oligosaccharidoses is to evidence abnormal oligosaccharides excreted in urine, usually performed by the poorly sensitive but efficient thin layer chromatography (TLC) method. Developing a tandem mass spectrometry (MS/MS) technique could be of great interest to replace TLC. METHODS: Abnormal underivatized oligosaccharides have been recently studied using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, allowing the unambiguous identification of oligosaccharidoses. Based on this previous work, we developed an advantageous and efficient liquid chromatography (LC)/MS/MS method using a more common triple quadrupole tandem mass spectrometer for oligosaccharides analysis. RESULTS: Oligosaccharidoses (n = 97) and control (n = 240) urine samples were analysed. A specific pattern was obtained for each oligosaccharidosis using this method. In urine, it allows not only the identification of all the oligosaccharidoses previously identified by TLC (fucosidosis, alphamannosidosis, aspartylglucosaminuria, GM1 gangliosidosis, sialidosis, galactosialidosis and Schindler disease), but also extends the field of diagnosis to mucolipidosis type II, Sandhoff disease, and ß-mannosidosis. The same technique was applied to 16 amniotic fluid supernatants from oligosaccharidosis-affected foetuses (n = 16) compared with 37 unaffected. All the affected foetuses could be clearly identified: sialidosis (n = 3), galactosialidosis (n = 4), aspartylglucosaminuria (n = 1), mucolipidosis type II (n = 4) or GM1 gangliosidosis (n = 4). This technique can be applied to early prenatal diagnosis as well as to the oligosaccharidosis screening in the case of non-immune hydrops fetalis. CONCLUSIONS: The method is quick and easy to run, with an LC analysis time of 13 min per sample. The quantitative validation could not be obtained in the absence of a specific standard and of a labelled internal standard for each compound. Even if this LC/MS/MS method is only qualitative, it is very specific and much more sensitive than TLC. It allows the urinary screening of oligosaccharidoses, even mild or late-onset forms, and the screening of antenatal forms in amniotic fluid. Copyright © 2017 John Wiley & Sons, Ltd.

The Susd2 protein regulates neurite growth and excitatory synaptic density in hippocampal cultures.

Complement control protein (CCP) domains have adhesion properties and are commonly found in proteins that control the complement immune system. However, an increasing number of proteins containing CCP domains have been reported to display neuronal functions. Susd2 is a transmembrane protein containing one CCP domain. It was previously identified as a tumor-reversing protein, but has no characterized function in the CNS. The present study investigates the expression and function of Susd2 in the rat hippocampus. Characterization of Susd2 during development showed a peak in mRNA expression two weeks after birth. In hippocampal neuronal cultures, the same expression profile was observed at 15days in vitro for both mRNA and protein, a time consistent with synaptogenesis in our model. At the subcellular level, Susd2 was located on the soma, axons and dendrites, and appeared to associate preferentially with excitatory synapses. Inhibition of Susd2 by shRNAs led to decreased numbers of excitatory synaptic profiles, exclusively. Also, morphological parameters were studied on young (5DIV) developing neurons. After Susd2 inhibition, an increase in dendritic tree length but a decrease in axon elongation were observed, suggesting changes in adhesion properties. Our results demonstrate a dual role for Susd2 at different developmental stages, and raise the question whether Susd2 and other CCP-containing proteins expressed in the CNS could be function-related.

Recurrent "outsider" intronic variation in the SLC5A6 gene causes severe mixed axonal and demyelinating neuropathy, cyclic vomiting and optic atrophy in 3 families from Maghreb.

Sodium dependent multivitamin transporter (SMVT) deficiency is a very rare autosomal recessive disorder characterized by multisystemic clinical manifestations due to combined biotin, panthotenic acid and lipoic acid deficiency. About 10 families have been described so far. Accurate diagnosis is crucial because of the possibility of a supplementation treatment with proven efficacy. Here we describe 4 new patients (3 additional families) originating from the same world region (Algeria, Maghreb). All patients, born form consanguineous parents, were homozygous carriers of the same intronic variation, outside of canonical sites, in the SLC5A6 gene encoding SMVT. RNA study in one family allowed confirming the pathogenic effect of the variation and re-classifying this variant of uncertain significance as pathogenic, opening the possibility of genetic counseling and treatment. The identification of the same variation in three distinct and apparently unrelated families is suggestive of a founder effect. The phenotype of all patients was very similar, with systematic optic atrophy (initially considered as a very rare sign), severe cyclic vomiting, and rapidly progressive mixed axonal and demyelinating sensory motor neuropathy.

Long term follow-up after haematopoietic stem cell transplantation for mucopolysaccharidosis type I-H: a retrospective study of 51 patients.

Mucopolysaccharidosis type I-H (MPS I-H) is a rare lysosomal storage disorder caused by α-L-Iduronidase deficiency. Early haematopoietic stem cell transplantation (HSCT) is the sole available therapeutic option to preserve neurocognitive functions. We report long-term follow-up (median 9 years, interquartile range 8-16.5) for 51 MPS I-H patients who underwent HSCT between 1986 and 2018 in France. 4 patients died from complications of HSCT and one from disease progression. Complete chimerism and normal α-L-Iduronidase activity were obtained in 84% and 71% of patients respectively. No difference of outcomes was observed between bone marrow and cord blood stem cell sources. All patients acquired independent walking and 91% and 78% acquired intelligible language or reading and writing. Intelligence Quotient evaluation (n = 23) showed that 69% had IQ ≥ 70 at last follow-up. 58% of patients had normal or remedial schooling and 62% of the 13 adults had good socio-professional insertion. Skeletal dysplasia as well as vision and hearing impairments progressed despite HSCT, with significant disability. These results provide a long-term assessment of HSCT efficacy in MPS I-H and could be useful in the evaluation of novel promising treatments such as gene therapy.

Prognostic value of electroencephalographic paroxysms in post-anoxic coma: A new regularity EEG-based score.

OBJECTIVES: Several electroencephalographic (EEG) features -mainly the reactivity of background activity-have been suggested as reliable predictors of outcome for patients with post-anoxic coma (PAC). However, EEG in PAC often contains abundant EEG paroxysms (EP) that may hinder the detection of background EEG activity. We aimed to identify the features, among the different paroxysmal and non-paroxysmal EEG patterns, that may predict the outcome of patients with PAC. METHODS: We retrospectively reviewed the clinical and EEG characteristics of 67 patients with PAC and selected those with abundant EP. We classified EP according to several features and assessed their prognostic value for survival at 15 days. We calculated a global regularity score, as the sum of the value (1 if regular, 0 if not) attributed to each of 4 features of EP (duration, morphology, amplitude, and frequency). RESULTS: The 35 patient-group with abundant EP showed a higher mortality than the group without abundant EP. Among 12 features of EP, four regularity features (regularity of EP duration, morphology, amplitude, and global regularity score) had a poor prognostic value. A global regularity score ≥ 3 showed a positive predictive value of 100 % for a poor outcome and a negative predictive value of 54 %, with good interrater consistency (Cohen's kappa = .63). CONCLUSIONS: The presence of EP and their regularity features in PAC patients are strongly associated with poor outcome. We propose a global regularity score, easily derived from visual EEG inspection, that may be a reliable prognostic tool for these patients. Prospective and larger studies are needed to confirm these findings.

Prospective cholestanol screening of cerebrotendinous xanthomatosis among patients with juvenile-onset unexplained bilateral cataracts.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder related to CYP27A1 biallelic mutations, leading to decreased synthesis of bile acids and increased cholestanol. Juvenile bilateral cataracts are one of the most common findings in the disease, frequently occurring before the onset of neurological manifestations. While early treatment with chenodeoxycholic acid can prevent the onset of neurological impairment, poor awareness of CTX accounts for a markedly delayed diagnosis. The objective of this study was to evaluate the utility of plasma cholestanol analysis at the moment of cataract diagnosis and before the onset of neurological impairment in CTX. METHODS: Multicenter prospective cohort study of patients with juvenile-onset unexplained bilateral cataracts recruited from seven French ophthalmology departments. Plasma cholestanol analysis was performed at diagnosis from January 2018 to January 2020. CYP27A1 genetic testing was performed at the ophthalmologist's discretion. Cholestanol levels were compared with those of a similar population of patients without cataracts (control cohort). RESULTS: 30 patients were finally recruited, with a mean age at cataract diagnosis of 7.1 years (± 4.8 SD, range 1-19 years). One patient had a very high cholestanol level (68 µmol/L, reference < 10) and carried two pathogenic heterozygous mutations in CYP27A1 confirming CTX. This patient was a 19-year-old female, reporting chronic diarrhea only in childhood, and diagnosed with bilateral posterior cataracts with cortical fleck-like opacities. Therefore, the incidence of CTX in our cohort of patients was 3.3%. Five further patients (5/29; 17.2%) had moderate elevations of cholestanol level (between 10.3 and 16.5 µmol/L), compared to 12/286 (4.2%) in the control cohort (p = 0.014) after adjustment for age. CONCLUSION: Our study argue for the relevance of plasma cholestanol CTX screening in all patients with juvenile-onset unexplained cataracts, even without other CTX identified manifestations. Whether moderate elevations of plasma cholestanol unrelated to CTX may be a risk factor for bilateral cataracts occurrence needs further examination.

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.