Zellweger Syndrome is the Most Likely Diagnosis
In an infant presenting with severe hypotonia, failure to thrive, generalized weakness, hyperglycemia, and cardiomyopathy, Zellweger syndrome is the most likely diagnosis among the options provided.
Clinical Reasoning
The constellation of findings in this case—severe hypotonia, failure to thrive, weakness, hyperglycemia, and cardiomyopathy—points strongly toward a peroxisomal biogenesis disorder, specifically Zellweger syndrome. This diagnosis is supported by the following key distinguishing features:
Characteristic Presentation of Zellweger Syndrome
Neonatal hypotonia with poor feeding is the hallmark presentation, occurring uniformly in affected infants and distinguishing it from later-onset conditions 1, 2, 3.
Failure to thrive and difficulty with weight gain are universal features that present in the neonatal period, consistent with this case 1, 4.
Hepatic dysfunction commonly manifests as hepatomegaly or elevated liver enzymes, which can contribute to metabolic derangements including hyperglycemia 1, 3, 5.
Cardiomyopathy has been reported in Zellweger syndrome variants, particularly in cases with prolonged survival 4.
Profound hypotonia is present from birth and is more severe than in most other conditions on the differential 2, 3, 4.
Why Other Diagnoses Are Less Likely
Angelman syndrome does not present with cardiomyopathy, hyperglycemia, or failure to thrive in infancy; it manifests later with developmental delay, ataxia, and characteristic behavioral features 6.
Nemaline myopathy (a congenital myopathy) presents with hypotonia and weakness but cardiac involvement is rare—only 6 of 143 cases in one series developed transient heart failure, and hyperglycemia is not a feature 6.
Kearns-Sayre syndrome is a mitochondrial myopathy that typically presents later in childhood with chronic progressive external ophthalmoplegia and pigmentary retinopathy, not in the neonatal period with this constellation of findings 6.
Spinal muscular atrophy presents with hypotonia and weakness but does not cause cardiomyopathy, hepatomegaly, or hyperglycemia; it is primarily a motor neuron disease without multisystem metabolic involvement 6.
Diagnostic Confirmation
Biochemical testing should measure very long chain fatty acids (VLCFA), which are markedly elevated in Zellweger syndrome due to absent peroxisomal beta-oxidation 1, 2, 3.
Additional metabolic markers include elevated cerotic acid, phytanic acid, and increased excretion of 3,6-epoxydicarboxylic acids 2, 4.
Platelet DHAP-AT activity (dihydroxyacetone phosphate acyltransferase) is deficient and provides a sensitive diagnostic assay 3, 5.
Genetic testing for PEX gene mutations confirms the diagnosis; mutations in PEX1 are most common, though PEX14 and other variants exist 2, 4.
Critical Clinical Pitfalls
Do not delay diagnostic testing while waiting for additional symptoms to develop—Zellweger syndrome is fatal in early life, with most patients dying before age 1 year, making prompt diagnosis essential for genetic counseling and family planning 1, 2, 4.
Do not confuse with glycogen storage diseases—while GSD type III can present with hypoglycemia, hepatomegaly, and cardiomyopathy, it causes hypoglycemia (not hyperglycemia) and typically presents later with less severe neonatal hypotonia 6.
Recognize the phenotypic spectrum—milder variants of peroxisomal disorders exist and may present later in childhood, but the severe neonatal presentation with multisystem involvement described here is classic for Zellweger syndrome 3, 5.
Prognosis and Management
Prognosis is poor, with death typically occurring in the first year of life from respiratory complications, liver failure, or seizures 1, 2, 4.
Supportive care is the only available treatment, focusing on seizure management, nutritional support, and symptomatic treatment of hepatic dysfunction 1, 2.
Genetic counseling is crucial as this is an autosomal recessive disorder with a 25% recurrence risk in future pregnancies 1, 2.