The proband, was a boy aged 14-years when the diagnosis of aldolase deficiency was established. He is the third child of an Albanian couple without consanguinity.
The boy was born after an uneventful pregnancy and delivery, and presented with normal growth and neurologic development. At the age of 2 years he was admitted to the hospital for a severe anemia which required blood transfusion. Unfortunately, no data was available regarding that episode.
At the age of 14 years and 9 months, the child presented a first episode of generalized tonic–clonic seizures associated with loss of consciousness and followed by dark ''coca-cola''–coloured urine. Laboratory examination revealed myoglobinuria with evidence of hypertransaminasemia, and hyperCPKemia (AST 4559 U/I normal 0–40; ALT 1198 U/l, normal 0–40; CPK 138,000 U/l, normal 0–170). At that time, echocardiography, abdomen ultrasound, brain CT, and EEG were performed at the "Mother Teresa" University Hospital Center in Tirana and no abnormality was detected.
His family history revealed that an older brother, previously diagnosed with epilepsy and rhabdomyolysis at the age of 14 years, died during a sudden status epilepticus at the age of 17 years.
Taking into consideration both clinical and family history, in the suspicion of metabolic disease, exome sequencing was performed and the homozygous pathogenic variant c.1001C > T (p.Ala334Val) of gene ALDOA was localized and classified as likely pathogenic (class 2) according to the recommendation of Centogene (Rostock, Germany) and ACMG (ACMG SF v2.0 2016 update). Polyphen software predicted this change to be as “probably damaging”. On the basis of this finding a diagnosis of GSD XII was done. Segregation studies confirmed the heterozygosity in both parents and in the younger brother.
At the age of 15 years, the boy presented two more critical episodes one month apart with subsequent rhabdomyolysis and myoglobinuria which resolved spontaneously. CPK values were 138,000 U/I and 11,560 U/I respectively. At this time, the patient was referred to the Center for Metabolic Diseases of the Salesi Children's Hospital, Ancona, Italy, for further evaluation. On admission, the child appeared in good general condition. He did not show developmental delays nor appreciable dysmorphic features. He weighed 41 kg (3° p), and was 156 cm tall (90° p). On physical examination, the patient had diminished muscle mass with normal muscle tone and mild dorsal-lumbar right convex scoliosis (Figs. 1 and 2). He did not show any motor limitations, but only mild diffuse myalgia, mainly in the lumbar area. He did not present hepatomegaly. Laboratory examinations revealed the following values: hemoglobin 11.1 g/dl; hematocrit 32.9%; MCV 83 fl, white-cell count 8310/mmc and platelet count 272,000/mmc. The CPK concentration was markedly elevated (14,000 U/l). The levels of the following were also abnormal: AST 465 U/l; ALT 375 U/l; lactate dehydrogenase 542 U/l (normal 0–325). Urinalysis and arterial blood gas analysis were normal. During hospitalization, the child presented two more critical episodes. The first episode occurred in the early morning, during sleep, in apyrexia. He presented with generalized tonic–clonic seizures which resolved after administration of rectal diazepam. Laboratory examination revealed severe metabolic acidosis (Ph 7.2, HCO3- 19 mmol/l, base excess -5.7 mmol/l, anion gap 15 mmol/l), mild renal insufficiency (creatinine level 0.95 mg/dl, normal 0.2–1.3), hyperuricemia (16.8 mg/dl, normal 2.5–7) and hyperCPKemia (33.306 U/l), and hypermyoglobinemia (1148 ng/ml, normal 0–110). Adequate hydration was practiced and rasburicase was prescribed with normalization of urinary biomarkers. An EEG was performed immediately after the crisis and no abnormalities were detected. In contrast, the EEG performed 24 h post-crisis showed sporadic wide slow waves. The second episode, similarly to the first, occurred early in the morning, during sleep. The patient presented metabolic acidosis (ph 7.28, HCO3- 28.7 mmol/l, anion gap 21, EB -7, lactic acid 7.6), hyperuricemia (13.2 mg / dl) and hyperCPKemia (41.870 U/l) and hypermyoglobinemia (1738 ng/ml). As with the previous episode he was treated with adequate hydration and rasburicase therapy.
While immediate resolution of metabolic acidosis and hyperuricemia was achieved, myoglobinuria and high rhabdomyolysis indices persisted, returning to baseline only in the following days (CPK 1612U /l, myoglobin 138 ng/ml). Taking into consideration the patient’s history of early morning seizures, in conjunction with metabolic acidosis, a normocaloric diet was put into place, with particular emphasis placed on the midnight meal consisting of slow-absorbing carbohydrates (cornstarch). This nutritional intervention was introduced alongside an anticonvulsant therapy consisting of Leviteracetam twice daily.
The patient was then referred to the Division of Metabolism at Ospedale Pediatrico Bambino Gesù in Rome for further diagnostic and therapeutic evaluations. The metabolic work-up was always normal, both in the acute phases and in the intervening periods, specifically plasma and urinary amino acids, plasmatic acylcarnitine profile, and urinary organic acids, chromatography of urinary carbohydrates. A 24-h fasting test was performed resulting in normal glycemia, however an elevation of CPK together with ST segment depression at ECG was noticed. After nutrition recovery, both ECG and CPK values normalized. At the same time, the boy presented mild symptoms of pharyngodynia and rhinorrhea and tested positive for Covid-19. In consideration of many studies highlighting the potentially positive effects of ketogenic diet on many neurological diseases and muscular GSD III, V, VII [10,11,12,13,14] ketogenic diet was started to the patient. After five months from the start of ketogenic diet, the patient did not experience any further metabolic decompensations, as reported by phone interviews.