Differential diagnosis in children with multisystem involvment: Mitochrondial and other complex metabolic pathologies

The purpose of this work was to develop and test a tool of clinical indicators to assist in diagnosis and referral of undiagnosed children with complex multisystem involvement. Three studies were conducted.

In the first study a chart of primary clinical indicators was created from literature on cerebral palsy (CP), Rett syndrome (RTT), metachromatic leukodystrophy (MLD), Krabbe disease, and mitochondrial disorders and cases of undiagnosed children. CP and RTT are established diagnostic entities while MLD, Krabbe, and mitochondrial disorders are less known. Primary clinical indicators were selected with 60% or more prevalence. The primary clinical indicators for CP are hypertonicity; quadriplegia, hemiplegia, or diplegia; and dyskinesia; for RTT are ataxia, apraxia, hand stereotypies, and regression; for MLD are hypertonia, hypotonia, initial gait disturbance, and regression; for Krabbe are hypertonia, regression, irritability, and primary feeding issues; for mitochondrial disorders are hypotonia, regression, three or more organ systems affected, primary feeding issues, and dysmorphism; for the 10 undiagnosed children are hypotonia and primary feeding issues. A category of "other" was added to the tool for the latter category.

In the second study the tool was assessed for validity and refined. Thirty-three subjects with known diagnoses were included. Primary clinical indicators were compiled and compared to the tool. CP and RTT were accurately identified, and with modifications to the tool, both leukodystrophies (changed from MLD) and mitochondrial disorders (regression and dysmorphism removed) also demonstrated good clinical utility.

The purpose of the third study was to assess the efficacy of the revised clinical indicator tool in guiding clinical diagnoses of complex multisystem disorders. Twenty-one subjects with diagnoses blinded to the primary researchers were included in a medical record review. CP demonstrated the greatest prevalence, and no subjects had RTT, MLD, or Krabbe. The tool was again revised by adding a category of "complex."

In conclusion the tool demonstrated the ability to differentiate CP and RTT with additional validation needed for complex multisystem disorders in future studies with greater subject number and geographical scope.