Investigations in Rare Treatable Disorders

Condition	Presentation	Key investigations	Treatment
Autosomal-recessive guanosine triphosphate (GTP) cyclohydrolase 1 (AR-GCH1) deficiency without hyperphenylalaninaemia (those with high blood phenylalanine will have been detected by neonatal screening test)	'Cerebral palsy'; oculogyric crises, tremulousness, bradykinesia	Avoid levodopa trial to prevent diagnostic confusion, phenylalanine loading test is simple to perform: 4 hour blood spot phenylalanine level will be high as will phenylalanine/tyrosine ratio. C5F pterins low, monoamine neurotransmitters may be normal. Definitive diagnosis is by either peripheral blood mononuclear or fibroblast GTP cyclohydrolase enzyme assay or directly through mutation analysis on DNA	BH4 (tetrahydrobiopterin), levodopa; 5-hydroxy-tryptophan and folinic acid will allow normal development if started sufficiently early
Adrenocorticotrophic hormone (ACTH) unresponsiveness	Recurrent encephalopathy with hypoglycaemia, secondary epilepsy. Joint hyperpigmentation may be subtle	↓ glucose, ↓ Cortisol, ↑ ACTH	Cortisol
Biotinidase deficiency (or biotin deficiency)	Epilepsy, developmental delay, various acquired neurological deficits (cerebrum, brainstem, cord), mimics Leigh syndrome (± alopecia, rash)	Brain and spinal cord MRI, urine organic acids, blood and C5F lactate, biotin trial, plasma biotinidase	Biotin
Biotin-responsive basal ganglia disease	Vague illness → rapid loss of motor skills → quadriparesis; seizures, akinetic, no speech	Brain MRI: head of caudate and putamen 'necrosis'. Response to biotin trial 5-10mg/kg/d. Mutations in SLC19A3	Biotin
Cerebrotendinous xanthomatosis	Combined central and peripheral nervous system degeneration. Xanthomata may not be apparent. Juvenile cataracts	Plasma cholestanol ↑	Chenodeoxycholic acid
Cobalamin disorders, especially deficiency of cobalamin complementation groups c and d	Infantile epilepsy, delay, hypotonia, poor head growth, encephalopathy, 'psychiatric', myelopathy (pyramidal and posterior column), neuropathy	Spinal cord MRI, especially T2 posterior columns; plasma homocysteine; urine methylmalonic acid	Hydroxycobalamin
DEND (delay, epilepsy, neonatal diabetes mellitus)	Neonatal diabetes mellitus, delay, epileptic spasms	KCNJ11 mutations	Sulphonylurea (tolbutamide)
Dopa-responsive dystonia (Segawa disease)	Dystonia any time from early childhood	Levodopa trial, CSF pterins and monoamine neurotransmitters	Levodopa/carbidopa
Familial haemophagocytic lymphohistiocytosis	May not show macrophage activation syndrome. Fever and multiple neurological presentations: acute disseminated encephalomyelitis (ADEM)-like, Aicardi-Goutieres-like and peripheral neuropathy. Brain lesions asymmetrical	Complete blood count and film; ↑ ferritin; bone marrow; CSF cells for perforin marker	Allogenic bone marrow transplant
Folate deficiency (cerebral folate deficiency)	Supposed manifestations include nonspecific neurodevelopmental delays and deviations ± autism	CSF 5 methyl-tetradydrofolate (5-MTHF) low with normal serum folate	Folinic acid
Guanidine methyltransferase (GAMT) deficiency	Epilepsy, learning disability, possible acquired movement disorder (may have false aminoaciduria, or glycoamino-glycanuria)	Urine guanidinoacetate ↑ ↓ Creatine peak on brain H-MRS ↓ Creatine peak on in vitro CSF H-MRS	Creatine
Glucose transporter 1 (GLUT1) deficiency	Epilepsy not drug-controlled: absences, myoclonus, drops; ± early infancy paroxysmal 'opsoclonus', movement disorder. Ataxia, especially intermittent ataxia. Paroxysmal exertional dyskinesia	Fasting blood glucose immediately before CSF; low CSF glucose, low CSF/blood glucose ratio (0.19-0.49) and normal to low lactate	Ketogenic diet
Hashimoto encephalopathy	Older girls, seizures, stroke-like episodes, confusion, hallucinations	Anti-thyroperoxidase (anti-TPO) antibodies	Corticosteroids
Hyperekplexia	Neonatal apnoeas, stiffness, startle, nose-tap head retraction	Video surface EMG as part of ictal EEG/ECG; GLRA1. GlyT2 (SLC6A5) mutations	Clonazepam
Long-QT syndromes (LQT)	'Seizures' especially fright or sound startle induced, including nocturnal in sleep	ECG for QTc but may not always be long; implantable ECG monitoring; LQT mutation analysis	Beta blockers (± implantable defibrillator)
Myasthenia (congenital myasthenia)	Neonatal and infantile apnoeas, floppy baby	Edrophonium test. Stimulation single-fibre EMG (stimSFEMG) orbicularis oculi. Mutation analysis at specialist myasthenia laboratory	Pyridostigimine, etc.
Neuroborreliosis	Facial palsy, headache, meningitis without neck stiffness, ADEM-like, arterial ischaemic stroke, cerebellar ataxia, sensorimotor neuropathy	Borrelia titres, CSF, polymerase chain reaction borrelia	Specific antibiotics (such as ceftriaxone)
Neuroleptospirosis	Aseptic meningitis, cerebellar ataxia, neuropathy; hepato-renal dysfunction + conjunctival injection	Leptospira serology	Specific antibiotics (such as crystalline penicillin)
Ornithine transcarbamylase heterozygotes	Stroke-like episodes, headache, vomiting, acute encephalopathy	Blood ammonia, urine orotic acid and uracil	Low protein diet, etc.
Paroxysmal extreme pain disorder	Neonatal flushing, apnoea, anoxic seizures, tonic attacks	Home video, SCN9A mutation analysis	Carbamazepine
Poisoning (exogenous and endogenous): accidental ingestion or exposure, covert poisoning; gut and urinary tract bacterial overgrowth syndromes)	Acute encephalopathy, seizures, syncope, central and peripheral deficits, bizarre history	EEG, ECG, radiography knees, abdominal imaging, urine culture, blood film, ammonia (and toxicology of course for tricyclics, etc.)	Remove source
Pyridoxine-dependent epilepsy	Neonatal, infantile or later infantile seizures, polymorphous may be Dravet-like	Pyridoxine trial (or pyridoxal phosphate trial), urine ↑ alpha-aminoadipic semialdehyde (α-AASA), ↑ pipecolic acid in all body fluids, antiquitin (ALDH7A1) gene mutation (check alkaline phosphatase to exclude untreatable hypophosphatasia)	Pyridoxine
Pyridoxal phosphate-responsive seizures	Neonatal seizures, usually suppression-burst EEG (not yet known if infantile, late infantile or childhood presentation possible)	Pyridoxal phosphate trial. If seizures cease investigate as in pyridoxine-dependent epilepsy; if α-AASA and pipecolic acid normal go to PNPO gene (pyridoxal-5'-phosphate may also be measured in CSF)	Pyridoxal phosphate
Pyruvate dehydrogenase (PDH) deficiency	'Mitochondrial' presentations, episodic ataxia, dystonia, flaccid paralysis	MRI altered signal in globus pallidus; CSF lactate may be normal but lactate/pyruvate ratio low; fibroblast PDH	Ketogenic diet
Riboflavin-responsive multiple acyl-coenzyme A dehydrogenase deficiency (MADD)	Encephalopathy, muscle weakness or both. Might be multiple sclerosislike; may be earlier history of cyclical vomiting	Urine acylcarnitines, mutations in one of the electron transfer flavoprotein genes	Riboflavin
Sepiapterin reductase deficiency	'Cerebral palsy' oculogyric crises (might be mistaken for atypical absences), dystonic episodes, learning disability	Although dopa responsive, avoid levodopa trial if possible; CSF monoamine neurotransmitters and biopterins + specific analysis of CSF sepiapterin	Levodopa, carbidopa, 5-hydroxytryptophan ± BH4
Serine synthesis disorders (phosphoserine aminotransferase deficiency is treatable postnatally)	Early epileptic seizures, microcephaly	CSF amino acids for low serine and glycine	Serine and glycine supplements
Ubiquinone (CoQ10) deficiency	Clinically and probably genetically heterogeneous. Severe infantile encephalopathy with renal disease, encephalomyopathy, myopathy, ataxia, cerebellar atrophy	White cell CoQ10, muscle electron transport chain studies, muscle CoQ10, fibroblast CoQ10	Oral CoQ10 (only some variants are treatable: arguably CoQ10 should be used as a therapeutic trial)
Vitamin B12 deficiency (may not be as obvious as it might seem -see also Cobalamin disorders, above)	Infantile tremor or odd movement disorder, mother vegan	B12 organic acids	Hydroxycobalamin
	Subacute combined degeneration of the cord - may be difficult because of psychosocial factors	Spinal cord MRI for posterior column signal change, B12, organic acids	Hydroxycobalamin
Vitamin E deficiency (especially isolated vitamin E malabsorption)	Ataxia, neuropathy, retinopathy, spinocerebellar features, deafness	Blood vitamin E	Vitamin E
Wilson disease	Older child and adolescent, almost always Kayser-Fleischer rings, behavioural, extra pyramidal, tremor dysarthria, basal ganglia signal change on MRI	Ceruloplasmin, urine and plasma Cu, 24-h urine Cu, liver Cu if necessary. ATP7B gene mutation once neurological investigations have established diagnosis (too many mutations to screen)	D-penicillamine, zinc, trientine

Further reading

• Biancheri R, Cerone R, Rossi A. (2002) Early-onset cobalamin C/D deficiency: epilepsy and electroencephalographic features. Epilepsia 43: 616-622.
• Biancheri R, Cerone R, Schiaffino MC. (2001) Cobalamin (Cbl) C/D deficiency: clinical, neurophysiological and neuroradiologic findings in 14 cases. Neuropediatrics 32: 14-22.
• Carmel R, Green R, Rosenblatt DS, el al. (2003) Update on cobalamin, folate, and homocysteine. Hematology Am Soc Hematol Edue Program, 62-81.
• Cooper EC, Pan Z. (2007) Pulling an end to DEND: a severe neonatal-onsel epilepsy is treatable if recognized early. Neurology 69: 1310-1311.
• Gallagher RC, Van Hove JL, Scharer G, et al. (2009) Folinic acid-responsive seizures are identical 10 pyridoxine-dependent epilepsy. Ann Neurol 65: 550-556.
• Gamstrop L. (1991) Lyme borreliosis from a patient's view-point. Stand J Infect Dis Suppl 77: 15-16.
• Olsen RK, Olpin SE, Andresen BS, et al. (2007) ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain 130: 2045-2054.
• Ozand PT, Gascon GG, AJ Essa M, et al. (1998) Hiotin-responsive basal ganglia disease: a novel entity. Brain 121: 1267-1279.
• Rotig A, Mallet J, Rio M, et al. (2007) Infantile and pediatric quinone deficiency diseases. Mitochondrion 7 Suppl. S112-S121.
• Saudubray JM, Sedel F, Walter JH. (2006) Clinical approach to treatable inborn metabolic diseases: an introduction J. Inherit Melab Dis 29: 261-274.
• Sedel F, Lyon-Caen O, Saudubray JM. (2007) Therapy insight: inborn errors of metabolism in adult neurology—a clinical approach focused on treatable diseases. Nat Clin Pracst Neurol 3: 279-90.
• Surtees R, Wolf N. (2007) Treatable neonatal epilepsy. Arch Dis Child 92: 659-661.
• Tuchman M, Lee B. Lichter-Konecki U, et al. (2008) Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab 94: 397-402.
• Zeng WQ, Al-Yamani E, Acierno JS Jr, et al. (2005) Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Am J Hum Genet 77: 16-26.

Source:
Mary D. King, 2009. A Handbook of Neurological Investigations in Children. 1 Edition. Mac Keith Press.

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Cite this: Cite this: ICNApedia contributors.Investigations in Rare Treatable Disorders. ICNApedia, The Child Neurology Knowledge Environment. 30 June 2024. Available at: https://icnapedia.org/knowledgebase/articles/investigations-in-rare-treatable-disorders Accessed  30 June 2024.