Eda Jazexhiu-Postoli

BACKGROUND Gaucher disease (GD) is a lysosomal storage disorder caused by mutations in the glucosylceramidase beta 1 (GBA1) gene, with a wide range of clinical manifestations. Type 2 GD, the acute neuronopathic form, is the most severe and has historically been considered a distinct clinical entity. Emerging evidence suggests a broader phenotypic spectrum, including intermediate forms that do not fully align with the diagnostic criteria for either type 2 or type 3 GD. Here, we describe an Albanian patient with an unusual intermediate type 2-3 phenotype, homozygous for the rare GBA1 complex allele p.[His294Gln;Asp448His] that is frequently found in Balkan populations. Although this genotype is typically associated with early-onset type 2 GD and death within the first 2 years of life, our patient developed neurologic symptoms at 15 months and survived until age 5. CASE REPORT A male Albanian infant presented at 4 months of age with hepatosplenomegaly and thrombocytopenia. Genetic testing revealed homozygosity for the rare GBA1 complex allele p.[His294Gln;Asp448His]. Enzyme replacement therapy, initiated at 7 months, led to temporary improvement of visceral and hematological symptoms. Neurologic manifestations - including oculomotor apraxia, dystonia, and seizures - emerged at 15 months. Despite continued enzyme replacement therapy and supportive care, the patient's neurologic condition progressively worsened, and he died at age 5 due to disease progression and pulmonary complications. CONCLUSIONS This case reinforces the concept that type 2 GD exists on a phenotypic spectrum, rather than as a uniform clinical entity, and underscores the broad genotype-phenotype variability in GD.

Background: Fructose‐1,6‐bisphosphatase (FBPase) deficiency is a rare autosomal recessive disorder of gluconeogenesis caused by biallelic pathogenic variants in the FBP1 gene. It presents with episodic hypoglycemia, lactic acidosis, and ketone body abnormalities, particularly during catabolic stress, but often mimics more common metabolic disorders, leading to diagnostic delays. Case Presentation: We describe the first genetically confirmed Albanian case of FBPase deficiency in a 3‐year‐old girl, born to nonsanguineous parents. The patient presented with recurrent episodes of vomiting, hypoglycemia, and metabolic decompensation since infancy. At her most severe presentation, she was admitted in a subcomatose state with profound hypoglycemia (35 mg/dL) and lactic acidosis (pH 6.9) without ketonuria. Whole exome sequencing identified a homozygous pathogenic FBP1 variant NM_000507.3(FBP1): c.472C > T; p. (Arg158Trp), a recurrent missense mutation associated with significant phenotypic variability. Parental testing confirmed autosomal recessive inheritance. Management and Outcome: Emergency management included intravenous dextrose and bicarbonate for metabolic acidosis, followed by nutritional interventions. The patient was advised to avoid fasting for more than 8 h and to limit fructose intake. No further metabolic crises were observed after these interventions. Conclusion: This case highlights the clinical and genetic complexity of FBPase deficiency and underlines the importance of genomic diagnostics in children with unexplained hypoglycemia and metabolic acidosis. Early diagnosis allows effective dietary management and prevents recurrent life‐threatening episodes. As the first reported case in Albania, it contributes to the growing recognition of FBPase deficiency as an underdiagnosed but treatable metabolic disorder.