**Background:** Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder caused by deficiency of the branched-chain alpha-keto acid dehydrogenase complex, leading to toxic accumulation of leucine, isoleucine, and valine. It occurs in approximately 1 in 185,000 live births globally. MSUD has five phenotypes: classic, intermittent, intermediate, thiamine-responsive, and E3 deficient. Acute encephalopathy (AE) is a severe, rapid-onset neurological dysfunction characterized by altered mental status, seizures, and coma, with diverse etiologies including infections, metabolic disturbances, and toxins. This case presents a rare instance of AE as the initial manifestation of intermediate MSUD in a teenager.
**Methods:** This is a single case report of a 10-year-old female, previously healthy, from a rural area of Portugal, who presented to the Emergency Department with behavior changes, visual hallucinations, and disorientation following a four-day viral illness (fever, myalgia, cough, rhinorrhea). Her 18-year-old sister had similar symptoms and was admitted with seizures and altered mental state. The patient underwent physical examination, laboratory analysis (including serum electrolytes, glucose, blood gas, virologic panel, C-reactive protein, white cell count, urine toxics, liver transaminases, coagulation studies, and cerebrospinal fluid analysis), brain CT scans, EEG, and ICP monitoring. Treatment included empiric ceftriaxone, oseltamivir, acyclovir, methylprednisolone (30 mg/kg for five days), intravenous immunoglobulin, plasmapheresis, tocilizumab, thiamine, and decompressive craniectomy for refractory intracranial hypertension. Genetic diagnosis was established via trio exome sequencing.
**Key Results:** The patient presented with fluctuating mental status (GCS 10-15) and bradycardia, progressing to seizures and GCS 8 on day 1, requiring intubation. Initial labs showed slight metabolic acidosis (pH 7.22, pCO2 44 mmHg, HCO3- 18 mmol/L) with increased anion gap (20 mEq/L). Nasopharyngeal swab was positive for influenza A. CSF analysis was normal. Brain CT on day 1 was normal; on day 4, MRI showed diffuse cytotoxic edema. ICP peaked at 70 mmHg, refractory to osmotic therapy. Decompressive craniectomy was performed on day 5. She required noradrenaline support from days 6 to 14. Hospitalization lasted 59 days (32 in PICU). After rehabilitation, she was discharged seven months later with only facial peripheral palsy and mild dysarthrophonia. Her sister died on day 4. Trio exome sequencing revealed a homozygous pathogenic variant c.659C>T (p.(Ala220Val)) in the BCKDHA gene, confirming MSUD. Plasma amino acids after recovery showed elevated valine (399 μmol/L, NR 88-290), leucine (273 μmol/L, NR 68-158), isoleucine (128 μmol/L, NR 36-82), and alloisoleucine (17 μmol/L, NR 1.2-3.4), consistent with intermediate MSUD.
**Clinical Implications:** This case underscores that non-classical MSUD can present in adolescence with acute encephalopathy triggered by infection (influenza A), even with negative newborn screening (false negatives can occur, as in Portugal's universal screening since 2005). The rapid progression and familial occurrence highlight the need for high clinical suspicion in unexplained AE, especially with concurrent sibling illness. Early recognition and aggressive management (including ICP monitoring, decompressive craniectomy, and metabolic support) are critical, but treatment should not be delayed for definitive diagnosis. Long-term management includes a protein-restricted diet with BCAA-free amino acid supplements and emergency protocols for intercurrent illness. Genetic counseling is essential for affected families.