Gaucher Disease or Acid Sphingomyelinase Deficiency? The Importance of Differential Diagnosis.

Background: Gaucher disease is a lysosomal storage disorder caused by functional glucocerebrosidase enzyme deficiency. Hepatosplenomegaly and hematological complications are found in both Gaucher disease and Acid Sphingomyelinase Deficiency, which is caused by acid sphingomyelinase dysfunction. The possible overlap in clinical presentation can cause diagnostic errors in differential diagnosis. For this reason, in patients with an initial clinical suspicion of Gaucher disease, we aimed to carry out a parallel screening of acid sphingomyelinase and glucocerebrosidase. Methods: Peripheral blood samples of 627 patients were collected, and enzymatic activity analysis was performed on both glucocerebrosidase and acid sphingomyelinase. The specific gene was studied in samples with null or reduced enzymatic activity. Specific molecular biomarkers helped to achieve the correct diagnosis. Results: In 98.7% of patients, normal values of glucocerebrosidase activity excluded Gaucher disease. In 8 of 627 patients (1.3%), the glucocerebrosidase enzymatic activity assay was below the normal range, so genetic GBA1 analysis confirmed the enzymatic defect. Three patients (0.5%) had normal glucocerebrosidase activity, so they were not affected by Gaucher disease, and showed decreased acid sphingomyelinase activity. SMPD1 gene mutations responsible for Acid Sphingomyelinase Deficiency were found. The levels of specific biomarkers found in these patients further strengthened the genetic data. Conclusions: Our results suggest that in the presence of typical signs and symptoms of Gaucher disease, Acid Sphingomyelinase Deficiency should be considered. For this reason, the presence of hepatosplenomegaly, thrombocytopenia, leukocytopenia, and anemia should alert clinicians to analyze both enzymes by a combined screening. Today, enzyme replacement therapy is available for the treatment of both pathologies; therefore, prompt diagnosis is essential for patients to start accurate treatment and to avoid diagnostic delay.

Reducing agalsidase beta infusion time in Fabry patients: low incidence of antibody formation and infusion-associated reactions in an Italian multicenter study.

BACKGROUND: Fabry disease is a rare progressive X-linked lysosomal storage disease caused by mutations in the GLA gene that encodes α-galactosidase A. Agalsidase beta is a recombinant enzyme replacement therapy authorized in Europe at a standard dose of 1.0 mg/kg intravenously every other week at an initial infusion rate of ≤ 0.25 mg/min until patient tolerance is established, after which the infusion rate may be increased gradually. However, specific practical guidance regarding the progressive reduction in infusion time is lacking. This study investigated a new and specific protocol for reducing agalsidase beta infusion time in which a stable dosage of 15 mg/h is infused for the first four months, and the infusion rate is increased progressively from 15 to 35 mg/h for the subsequent four infusions. The shortest infusion time is reached after six months and maintained thereafter. The incidence of infusion-associated reactions (IARs) and the development of anti-drug antibodies were analyzed, and the disease burden and the clinical evolution of the disease at 12 months were evaluated. RESULTS: Twenty-five of the 31 patients were naïve to enzyme or chaperone treatment at baseline and six patients had been switched from agalsidase alfa. The reduced infusion time protocol was well tolerated. Only one patient exhibited an IAR, with mild symptoms that resolved with low-dose steroids. Six patients globally seroconverted during treatment (4 with a classic phenotype and 2 with late-onset disease). All but three patients were seronegative at month 12. All patients were stable at the study's end (FAbry STabilization indEX value < 20%); reducing infusion time did not negatively impact clinical outcomes in any patient. The perceived medical assessment showed that the quality of life of all patients improved. CONCLUSIONS: The study demonstrates that reducing agalsidase beta infusion time is possible and safe from both an immunogenic and clinical point of view. The use of a low infusion rate in the first months when the probability of onset of the development of antibodies is higher contributed to very limited seroconversion to antibody-positive status.

Positive Impact of Home ERT for Mucopolysaccharidoses and Pompe Disease: The Lesson Learnt from the COVID-19 Pandemic.

OBJECTIVE: Patients with Lysosomal disorders (LSDs) are treated with regular infusions of enzyme replacement therapy (ERT). During the COVID-19 pandemic, home treatment was permitted. This study aimed at monitoring the patients' compliance with home therapy and its effects on physical, psychological, and relational issues. Moreover, we also tested the possible impact of home therapy on familial relationships and contacts with the referral hospital. MATERIALS AND METHODS: Thirteen patients with Pompe disease (N = 8) and MPS (N = 5) were tested through an online questionnaire designed to assess their level of appreciation and satisfaction with home therapy and their feelings about the referral centre and psychological support provided. RESULTS: Most of the patients (84%) stressed the positive impact of home therapy. All patients described a significant reduction in stressful conditions associated with the need to attend the hospital every week or two. CONCLUSIONS: Home ERT leads to a clear improvement in "daily life skills", as represented in our by sample by positive feelings, better emotional self-control, and an increased ability to understand the feelings of relatives. Our data underline the paramount positive effect home ERT has on both patients and their families.

Balance impairment in cerebrotendinous xanthomatosis: Ankle strategy deficit. A case study.

BACKGROUND: Cerebrotendinous xanthomatosis is a rare autosomal-recessive lipid storage disorder causing an elevation in cholestanol and cholesterol levels and their deposition in the central nervous system and tendons with consequent posture and gait disturbances. METHODS: This report shows the case of a 36-year-old male affected by Cerebrotendinous xanthomatosis with static and dynamic instability. We aimed to provide an instrumented quantification of quiet upright standing using a piezoelectric force platform measuring the variations of center of pressure with the foot position 10 cm and 20 cm apart or extra-rotated with an opening angle of 30°, with eyes open or closed. The area of center of pressure and the length of its trajectory in the anterior-posterior and medial-lateral directions were computed. The temporal variability of center of pressure was evaluated by means of the Root Mean Square. FINDINGS: In comparison with a control group, the area, the trajectory length of center of pressure in anterior-posterior and medial-lateral directions and the temporal variability increased in all static conditions. Intra-patient comparison showed that foot position 10 cm apart was the position that most influenced stability causing a marked worsening of area and trajectory length of center of pressure in both anterior-posterior and medial-lateral directions, particularly for the eyes closed condition. INTERPRETATION: We found a large static instability due to internal neural and biomechanical constraints causing an insufficiency of ankle strategy. A physical therapy program based on instrumented proprioceptive exercises is to be implemented to teach the use of a hip strategy.

Higher frequency of TMEM199-CDG in the southern mediterranean area is associated with c.92G>C (p.Arg31Pro) mutation.

Congenital disorders of glycosylation (CDG) are genetic multisystem diseases, characterized by defective glycoconjugate synthesis. A small number of CDG with isolated liver damage have been described, such as TMEM199-CDG, a non-encephalopathic liver disorder with Wilson disease-like phenotype. Only eight patients with TMEM199-CDG have been described including seven Europeans (originating from Greece and Italy) and one Chinese. Three patients from southern Italy (Campania) shared the same known missense mutation pathogenetic variant NM_152464.3:c. 92G > C (p.Arg31Pro), also found in a Greek patient. Here we report a new patient from southern Italy (Sicily), with a homozygous c.92G > C p.(Arg31Pro) variant in TMEM199. The patient's phenotype is characterized by mild non-progressive hepatopathy with a normal hepatic echo structure. A persistent increase in serum transaminases, total and low-density lipoprotein cholesterol and low serum ceruloplasmin and copper levels and normal urinary copper excretion were observed. Matrix-assisted laser desorption/ionization mass spectrometry analyses showed abnormal N- and O- protein glycosylation, indicative of a Golgi processing defect and supporting the function of TMEM199 in maintaining Golgi homeostasis. TMEM199-CDG is an ultra-rare CDG relatively frequent in the southern Mediterranean area (7 in 9 patients, 77%). It is mainly associated with the c.92G > C (p.Arg31Pro) pathogenetic allele globally reported in 4 out of 7 families (57%), including one from Greece and three unrelated families from southern Italy. The almost uniform clinical phenotype described in patients with TMEM199-CDG appears to reflect a higher prevalence of the same variant in patients from the southern Mediterranean area.

Dihydropyridine Reductase Deficiency: Acute Encephalopathy Related to Folinic Acid Treatment Interruption in a Girl.

We reported the case of acute encephalopathy related to colonic acid treatment interruption in a 12-year-old female child presenting to our unit with episodes of vomiting, headache, irritability, acute confusional state, seizures, and left lower limb hypotonia. Brain magnetic resonance imaging (MRI) showed signs of vasogenic and cytotoxic edema at the cerebellar level bilaterally, and lesions at the temporo-occipito-parietal right level, temporomandibular left, and right thalamic with swelling of the convolutions and reduced differentiation between white and gray matter. The patient had suspended the folinic acid treatment at least 6 months before the present admission. The relation between the clinical signs presented by the girl and folic acid deficiency was confirmed by the result of laboratory assessment and by the answer to the notable clinical improvement with the renewal of folinic acid treatment. Dihydropteridine reductase (DHPR) deficiency is a rare autosomal recessive genetic disorder caused by the quinoid dihydropteridine reductase (QDPR) gene mutations. DHPR deficiency impairs the synthesis of the tetrahydrobiopterin (BH4), an essential cofactor for the hydroxylation of the aromatic amino acids phenylalanine, tyrosine, and tryptophan. When not precociously treated, the disorder may present whit severe neurologic impairment including developmental delay/intellective disability (DD/ID), microcephaly, seizures, movement disorders, cerebral palsy, and other neurological impairments. The clinical and neuroradiologic anomalies observed in our case were unusual, with signs previously unreported in patients with folic acid deficiency. The present case shows that the clinical presentation and MRI anomalies of the cerebral folic acid deficiency may be various and unusual compared with those reported in the literature, and it confirms the usefulness of the continuation of folinic acid treatment during the course of the disorder in patients with DHPR deficiency.

On clinical findings of Bickerstaff's brainstem encephalitis in childhood.

A short review on the clinical presentation of pediatrics cases of Bickerstaff brain encephalitis emphasizing the broad clinical spectrum of the disease. Cases of pediatric Bickerstaff's brainstem encephalitis collected on three electronic medical databases (PubMed, Cochrane Library and Scopus Web of Science) are reviewed. The inclusion criteria of the cases were based on the clinical characteristics of the disorder in the pediatric age. We reviewed 20 articles on Bickerstaff's brainstem encephalitis, identifying 40 pediatric cases focused on the clinical symptoms. We saw that the prevalence was higher in male subjects, and the median age at diagnosis was 8 years. The phenotype of pediatrics patients was similar to previously published literature. We identify three cases of overlapping forms between Bickerstaff brain encephalitis and Guillain-Barré Syndrome in patients with lower limbs weakness and typical signs of Bickerstaff brain encephalitis, suggesting a combined involvement of the central and peripheral nervous system. Although there is no defined data on incidence and prevalence in the literature, Bickerstaff's brainstem encephalitis appears to be a rare disorder, especially in children. The incidence of Bickerstaff brain encephalitis and Guillain-Barré Syndrome, and Miller Fisher Syndrome has been underrated in the past, primarily due to an underestimation of the forms with a Peripheral Nervous System involvement. Bickerstaff brain encephalitis usually has a rapid and acute onset within 2-4 weeks, characterized by a typical picture of ophthalmoplegia, hyperreflexia, cerebellar symptoms as ataxia. The subsequent manifestations of hyperreflexia or consciousness disturbances as drowsiness, sleepiness, or coma, indicative of central involvement, suggest a Bickerstaff brain encephalitis clinical diagnosis.

COVID-19 Pandemic Outbreak and its Psychological Impact on Patients with Rare Lysosomal Diseases.

BACKGROUND: Lysosomal storage disorders (LSDs) are rare, chronic, progressive multisystem diseases implying severe medical issues and psychological burden. Some of these disorders are susceptible to a treatment, which is administered weekly or every other week, in a hospital. During the COVID-19 (Corona Virus Disease 2019) pandemic lockdown, patients with LSDs on enzyme replacement therapy (ERT) missed their scheduled access to the Day Hospital to get their treatment. METHODS: Based on the feeling that our patients were experiencing profound distress, we designed a structured telephone interview with the aim to evaluate how, and to which extent, the pandemic outbreak was changing their behavior and feelings about their chronic disease, the impact on therapies, and future expectations. The same interview was administered to an age-matched control group. RESULTS: All interviewed people experienced an increase of anxiety, worries, and uncertainty fostered by incessant media updates. Moreover, a striking similarity emerged between the groups regarding forced home reclusion and the profound feeling to be excluded by normal life, well-known to those affected by a chronic rare disease. CONCLUSIONS: Although no statistically significant difference was found compared to controls, we felt that the reactions were qualitatively different, underlining the fragility and isolation of such patients.

Deciphering the Invdupdel(8p) Genotype-Phenotype Correlation: Our Opinion.

The 8p inverted duplication/deletion is a rare chromosomal rearrangement clinically featuring neurodevelopmental delay, mild to severe cognitive impairment, heart congenital defects and brain abnormalities. Patients affected also present typical facial dysmorphisms and skeletal malformations, and it is thought that the composite clinical picture may fall into the chromosomal rearrangement architecture. With the major aim of better framing its related clinical and diagnostic paths, we describe a patient carrying a de novo invdupde[8p] whose clinical features have not been described so far. Hence, through an extensive genotype-phenotype correlation analysis and by reviewing the dedicated scientific literature, we compared our patient's features with those reported in other patients, which allows us to place our proband's expressiveness in an intermediate area, widening the scope of the already known invdupde[8p] genotype-phenotype relationship.

Genotype-phenotype variable correlation in Wilson disease: clinical history of two sisters with the similar genotype.

BACKGROUND: Wilson disease (WD) is an Autosomal-Recessive disorder due to mutations of ATP7B gene on chromosome 13q14.3. Inadequate protein function leads to low ceruloplasmin blood levels and copper accumulation in liver, basal ganglia and chornea. Main clinical manifestations are hypertransaminasemia, tremors, dysarthria, dystonia and psychiatric symptoms. The phenotypic variability in WD is considerable and its onset can be heterogeneous: the most common type in childhood is the hepatic involvement, followed by the neurological one or others. The presence of a genotype-phenotype correlation has not yet been fully demonstrated. The phenotypic variability may be explained by the intervention of other modifier genes regulating copper metabolism in the presence of mutations ATP7B. CASE PRESENTATION: A streaking phenotypic variability was observed in two Sicilian sisters carrying the same genotype for ATB7B gene [c.3207C > A / c.3904-2A > G]. Although both started to present signs at age 10 years, onset was characterized by neurological signs in the first (tremors, motor incoordination, language and cognitive impairment), while liver involvement has been the only sign in the other. They started the same chelation therapy. After a 20-year follow-up the former is severely affected (MRI evidence of basal ganglia copper deposits and hyperchogenic liver, thrombocytopenia), while the latter presents only a moderate liver enlargement. In literature, the splice mutation c.3904-2A > G is also reported in Egypt population, associated with acute liver failure or chronic hepatic disease, and it could be typical of Mediterranean area, not being reported in other geographical zones. CONCLUSION: Based on our clinical experience in Eastern Sicily, there is a considerable phenotypic variability in WD, even in the presence of an identical genotype. The mutation c.3904-2A > G could be associated with this phenotypic variability in Mediterranean population, but further studies should be conducted. This condition could be explained by the intervention of modifier genes regulating copper metabolism in the presence of defective ATP7B protein function. Further investigations on their role by Next Generation Sequencing or Whole Exome Analysis might have a profound impact on patients' management and in particular on therapy.