Toxicology & Metabolic Disease

Pantothenate kinase-associated neurodegeneration (PKAN)

• Also called Hallervorden-Spatz disease.
• Presents with dysarthria, spasticity, choreoathetosis, pigmented retinopathy, equinovarus deformity. 
• Secondary to pantothenate kinase gene (PANK2), Ch 20p13.
• Pathology: Iron accumulation within the globus pallidum and pars reticularis.
• Radiology: MRI will show an “eye of the tiger sign”; there is a hypointense lesion in the bilateral basal ganglia with a central hyperintensity which represents gliosis. 

Acid α-glucosidase deficiency (Pompe disease)

• Also known as glycogen storage disease type II or acid maltase deficiency, this autosomal recessive enzyme deficiency causes glycogen accumulation in lysosomes in organs, especially heart, muscle, and CNS.
  • Due to mutations of the GAA gene.
  • Infantile Pompe disease: presents in the first few months of life with hypotonia, macroglossia, failure to thrive, and cardiomyopathy.
  • Late-onset Pompe disease: variable severity of presentation, usually without cardiomyopathy. Can present from years to decades of life.
• Diagnosis: screening dried blood spots (DBS) and confirmatory GAA mutation genetic analysis.
• Pathology: PAS+ glycogen-filled lysosomes (vacuolar myopathy) on muscle biopsy.
• EMG may show myotonia.
• Treatment: enzyme replacement with alglucosidase alfa.

GLUT-1 deficiency

• Presents with refractory seizures in an infant with developmental delay, microcephaly, hypotonia, spasticity, ataxia, and dystonia.
• Pathophysiology: Mutation in SLC2A1 causes GLUT-1 deficiency, and thus unable to transport glucose into the brain, which results in low CSF glucose, while lactate is low-normal.
• Treatment: Ketogenic diet because it converts brain energy utilization from primarily glucose to an alternative fuel source of ketones.

Galactosemia

• Deficiency of Galactose 1-phosphate uridyl transferase.
• Intellectual disability, cataracts, failure to thrive, increased ICP, cerebral edema. Susceptible to E. coli infections.
• Treatment: eliminate lactose and galactose from the diet.

Urea cycle enzyme deficiencies

• Exam: If partial, adolescent or early adult-onset neuropsychiatric symptoms including episodic psychosis, depression, and bipolar disorder. These attacks frequently accompanied by gastrointestinal symptoms can be precipitated by high protein ingestion, periods of fever, and can be triggered by valproate
• X-linked UCD can present with strokes.

Phenylketonuria (PKU)

• Phenylalanine hydroxylase deficiency → phenylalanine (Phe) and derivatives build up → neuron death.
• Presents with delayed developmental, short stature, intellectual disability, mouse-like musty odor, possible seizures.
• Treatment: Diet restricted in Phe and protein.

Kearns-Sayre syndrome

• Mitochondrial inheritance disorder that presents with the triad of:
  1. Chronic progressive external ophthalmoplegia
  2. Retinitis pigmentosa
  3. Onset before 20 years of age.
• Also can commonly have heart block, short stature, sensorineural hearing loss, cerebellar ataxia and endocrine dysfunction.
• CSF will have elevated protein.
• As with many mitochondrial disorders, may see ragged red fibers on pathology.

Glutaric acidemia type I (GA 1)

• Deficiency of mitochondrial enzyme glutaryl-CoA dehydrogenase activity causes progressive macrocephaly, striatal necrosis, basal ganglia and frontotemporal degeneration.
• Elevated levels of serum GA, 3HGA, tGA.

Methylmalonic acidemia (MMA)

• deficiency of mitochondrial enzyme L-methylmalonyl-CoA mutase activity causes MMA and lactic acid build-up.
• Presents in infancy (after proteins added to diet) with developmental delay, lethargy, hypotonia, hepatomegaly, coma, and sometimes death.
• marked bilateral destruction of the globus pallidus
• Treatment: Low protein diet. Some are responsive to vitamin B12 injections.

Maple syrup urine disease

• Mitochondrial branched-chain α-ketoacid dehydrogenase deficiency →
• accumulation of branched-chain amino acids.
• Newborns with poor feeding, opisthotonic posturing, hypertonia, failure to thrive, and seizures. Urine with maple syrup scent.
• MR spectroscopy with a branched-chain amino acid spike.

Biotinidase deficiency

• Presents with alopecia, skin rash, developmental delay, visual/hearing impairment, and seizures.
• MRI shows hyperintensity in periventricular white matter and atrophy.
• Treatment: responds to high doses of oral biotin (vitamin B7).

X-linked adrenoleukodystrophy (X-linked ALD)

• ABCD1 gene/protein mutation → impaired peroxisomal β-oxidation → accumulation of very-long-chain fatty acids.
• Varied presentation, but affects bilateral white matter of the brain and adrenal glands. 
• Most common presentation is either childhood (4–8 years old) or adult form, with rapidly progressive ataxia, spasticity, personality change, visual/auditory deficits, and seizures.
• MRI is strongly suggesting, showing a bilateral posterior to anterior progression of white matter disease.

Zellweger syndrome

• Also known as cerebrohepatorenal syndrome.
• Occurs secondary to peroxisomal dysfunction due to a PEX gene mutation.
• Infantile form presents with hypotonia, craniofacial dysmorphisms, glaucoma, and sensorineural hearing loss.
• Blood work will show elevated very-long-chain fatty acids.

Homocystinuria

• Symptoms include myopia, dislocation of the lens at the front of the eye (lens subluxation), increased risk of blood clotting, osteoporosis, sometimes developmental delay and learning problems.
• Mutation in CBS gene 
  (cystathione-β-synthase)
• Buildup of homocysteine and methionine.
• Treatment: Low protein diet, Vitamin B6, and betaine, folate (B9), and cobalamin (B12).

Wilsons disease

• Copper accumulation due to errors of copper transport. Read more in the Movement Disorders Chapter.

Lysosomal storage disorders