New-Onset Ketosis-Prone Diabetes in an Adult with Spinal Muscular Atrophy Type III

A rare metabolic complication has been identified in a young adult with spinal muscular atrophy (SMA) type III, challenging conventional views of the disease as a purely neuromuscular disorder.

Published in JCEM Case Reports in July 2025, the case from Thailand presents a rare convergence of metabolic and neuromuscular disease: new-onset ketosis-prone diabetes (KPD). The patient, a 27-year-old male with genetically confirmed SMA type III, presented with polyuria and a 12-kilogram unintentional weight loss over three months. Laboratory findings confirmed diabetic ketoacidosis (DKA), with a fasting plasma glucose of 403 mg/dL, hemoglobin A1c of 12.0%, elevated β-hydroxybutyrate, and venous pH of 7.29.

Autoimmune and monogenic diabetes were ruled out; pancreatic autoantibodies (anti-GAD and anti-IA2) were negative, and a comprehensive gene panel detected no monogenic variants. A validated polygenic risk score incorporating 254 single-nucleotide polymorphisms indicated low genetic risk for type 2 diabetes, further supporting SMA-related metabolic dysfunction as the likely cause.

Treatment with intravenous fluids and insulin infusion led to resolution of DKA within eight hours, and insulin was tapered off within a month. Follow-up testing confirmed preserved β-cell function, with fasting and stimulated C-peptide levels of 1.2 and 6.2 ng/mL, respectively. The patient maintained glycemic control on oral metformin and a thiazolidinedione, with HbA1c improving to 6.4% at five months and no complications reported.

SMA as a Driver of Metabolic Disease

Though SMA is classically a motor neuron disease driven by SMN1 mutations, growing evidence highlights systemic metabolic involvement. This patient had severe sarcopenia (skeletal muscle index of 5.7 kg/m²; normal ≥7.0) and excess fat mass (31.3%; normal 10–20%) despite a normal BMI of 20.9 kg/m². Physical examination revealed disproportionate fat loss and muscle wasting in the limbs with calf hypertrophy, consistent with prior reports of altered muscle-fat composition in SMA.

The metabolic vulnerability in SMA likely stems from the central role of muscle in glucose disposal; reduced muscle mass and intramuscular fat promote insulin resistance. Additionally, animal models suggest altered pancreatic architecture—particularly alpha-cell predominance and hyperglucagonemia—which may accelerate ketone production. These changes are not seen in other neuromuscular disorders like Duchenne muscular dystrophy, suggesting a unique endocrine-metabolic profile in SMA.

Clinical Implications

Although KPD typically affects overweight, middle-aged men with family histories of diabetes, this case deviates sharply from that pattern. The patient was young, lean, and autoantibody-negative, and he demonstrated rapid β-cell recovery. Together, these features support a secondary diabetes mechanism rooted in SMA-specific metabolic dysfunction rather than coincidental onset.

The use of a thiazolidinedione alongside metformin is noteworthy. As a PPAR-γ agonist, the thiazolidinedione improves insulin sensitivity and may offer targeted benefit in settings of SMA-related lipotoxicity. While direct evidence in SMA remains limited, the rationale aligns with calls for more tailored metabolic management in this population.

This is only the third adult case to link SMA with DKA. As patients live longer thanks to disease-modifying therapies, clinicians should remain alert to non-neurologic complications, including atypical forms of diabetes. Regular screening for glucose and lipid abnormalities, early attention to sarcopenia, and consideration of insulin sensitizers may help prevent long-term metabolic consequences.

Ultimately, this case underscores that SMA is not just a motor neuron disease, but a multisystem disorder requiring broader clinical vigilance.

Reference

Thewjitcharoen Y, Nakasatien S, Kulkantrakorn K, Himathongkam T. Ketosis-prone Diabetes as a Presentation of New-onset Diabetes in a Patient With Spinal Muscular Atrophy Type III. JCEM Case Rep. 2025;3(9):luaf163. Published 2025 Jul 30.