Progressive loss of skills and dementia

Hypothyroidism
Untreated or unrecognized hypothyroidism is detected by thyroid function tests.

Phenylketonuria
Undetected phenylketonuria and related metabolic disorders are detected by plasma amino acids.

Vitamin B12 disorders
B12 disorders are suggested by plasma amino acids (homocysteine) and/or urine organic acids (methylmalonic).

Creatine synthesis disorders
GAMT deficiency may be detected by urine guanidinoacetate, but the fact that some creatine synthesis disorders may be detected only by finding a reduced creatine peak on proton MRS of brain means that this investigation should be considered whenever MRI is done for an unexplained condition with developmental regression.

Pelizaeus-Merzbacher disease and Pelizaeus-Merzbacher-like disease
They are examples of disorders with hypomyelination. Insofar as hypomyelination is defined as no change in lack of myelin over time, one might expect a truly static disorder rather than the clinical progression that may be evident.

Aicardi-Goutieres syndrome
It is an example of a disease which may be both progressive on imaging and non-progressive clinically, especially with mutations in RNASEH2B.

Deterioration in infancy - infantile

GM2 gangliosidosis

• Tay-Sachs disease presents with sound-startle, and the cherry-red spot at the macula prompts hexosaminidase estimation.
• Infantile Sandhoff disease is similar but with variable hepatosplenomegaly.

Krabbe disease

• An irritable infant with extended posture is surprisingly found to have absent tendon reflexes.
• Increased CSF protein suggests demyelinating neuropathy which is confirmed by very slow motor nerve conduction velocity.
• Confirmation of the diagnosis is by galactocerebrosidase beta-galactosidase estimation using a natural substrate.

GM1 gangliosidosis

• The dysmorphism is sufficient to prompt white cell enzyme assay looking for deficient beta-galactosidase.
• If urine glycosaminoglycans are tested for, keratan sulphate will be found to be increased.

Menkes disease

• Pili torti is usually a sufficient clue but in more subtle cases reduced serum copper and copper oxidase will show the diagnosis.
• Biochemical evaluation alone is needed when presymptomatic newborn infants are evaluated in known affected families: here abnormal plasma catecholamines reflect the disease.

Canavan disease

• Visual loss and megalencephaly will be identified by huge amounts of N-acetylaspartate on urine organic acid analysis.
• If MRI and H-MRS have been done first, the extensive white matter abnormality and N-acetylaspartate peak will be obvious
• Mild Canavan disease is a static disorder with only developmental delay and a modest N-acetylaspartic aciduria.

Molybdenum cofactor deficiency

• Milder cases of molybdenum cofactor deficiency may present in infancy not necessarily with dislocated lenses.
• Sulphite test of fresh urine will often but not always be positive.
• Plasma uric acid will be low, and total homocysteine should be estimated at the same time in case this is isolated sulphite oxidase deficiency.

Infantile neuronal ceroid lipofuscinosis

• This condition (most common in Finland) overlaps the first and second year of life in its time of presentation which is mainly around 1 year to 18 months.
• Normal development ceases before a subtle regression.
• Clinical clues include impaired visual awareness and repetitive movements of the hands rubbed together - these movements were originally described as knitting movements but closely resemble the so-called hand-washing movements of Rett syndrome.
• Short bursts of myoclonic activity (myoclonic epileptic seizures) may be subtle as developmental skills are gradually lost.
• The ERG declines in amplitude before the EEG flattens.
• MRI shows atrophy and increased signal in the thalami.
• EIectronmicroscopy of white cell pellets will show granular osmiophilic deposits (CRODs).
• Protein palmitoyl thioesterase (PPT) activity is reduced in plasma and in leukocytes - this will not normally be detected on routine white cell enzyme analyses and needs to be targeted specifically.
• As with serious neurodegenerative disorders in general, it is wise not to rely on a single abnormal neurological investigation. In this case, one should have at least the appearance of CRODs and very low PPT activity, and if possible, a CLN1 mutation.

Deterioration in infancy late infantile

Rett syndrome

• This is not a true regressive disorder but it certainly presents as loss of skills, particularly hand function, usually in the second year of life, with hand-washing movements and often bruxism and salivation, and acquired microcephaly.
• EEG is nonspecific but may show spikes and sharp waves at first only in sleep.
• Most affected girls have mutation in MECP2 but other genetic variants are recognized.

Late infantile neuronal ceroid lipofuscinosis

• This disorder may start beyond the age of 2 years but as it is in many countries one of the most common neurodegenerative disorders at about this age.
• It presents as epilepsy and may include stimulus-sensitive myoclonus.
• Ataxia and loss of skills may be attributed to either the epilepsy or the antiepileptic medication.
• Brain imaging shows cerebellar atrophy
• the most important simple investigation is slow stroboscope activation at 0.5 Hz during EEG, so this lest should never be omitted.
• In late infantile neuronal ceroid lipofuscinosis, giant occipital potentials are induced with each slowly repeated flash.
• Curvilinear inclusions on electronmicroscopy of white cell pellet or other tissues can be found and should be looked for, but it is easier to go direct to gene analysis of CLN2.

Metachromatic leukodystrophy

• The main clinical clue is evidence of peripheral neuropathy (impaired tendon reflexes) especially accompanying subtle dementia, cerebellar ataxia and bulbar signs.
• Toe-walking may be the presentation.
• The CSF protein is increased.
• Nerve conduction velocities will be slow
• metachromatic material found in tubular epithelial cells in urine
• aryl sulphatase A (ARSA) will be deficient in leukocytes or fibroblasts (a clinical diagnosis, aided by the demonstration of metachromatic material, will not be negated by normal white-cell ARSA).
• If brain MRI is done with gadolinium contrast, the cranial nerves may enhance (as they do in Krabbe leukodystrophy)

Infantile neuroaxonal dystrophy

• Completely normal development is followed by regression in central and peripheral nervous functions at around the end of the second year of life.
• There is usually a plateau before this regression.
• Clinical features include subtle ocular wobble, distal weakness with tendon hyporeflexia or areflexia and emerging extensor plantar responses.
• EEG shows diffuse beta activity but at first this is not obvious when it is still of rather low voltage
• Nerve conduction velocities are normal but EMC shows evidence of denervation
• Brain imaging reveals a degree of cerebellar atrophy
• Biopsies are necessary only if mutations are not found in PLA2G6.

Middle childhood

Sanfilippo disease

• In this common condition there is subtle dementia with more prominent behaviour difficulties, in particular aggression.
• Dysmorphisms such as difficulty extending the fingers are subtle.
• Urine glycosaminoglycans should reveal the diagnosis but 24 hour urine for heparan sulphate should be requested specifically if in doubt
• Gene tests are available, but the various genotypes are phenotypically indistinguishable.

Adrenoleukodystrophy

• By far the most common of the peroxisomopathies, this condition in boys may present with gradual loss of higher functions
• Not only may there be 'cortical' visual impairment, but choroiditis or other ocular abnormalities may be detected on ophthalmological examination
• Brain MRI usually shows predominantly posterior white matter change, the margins of which may enhance with contrast (there is an inflammatory reaction)
• Very long chain fatty acids should be increased in blood.

Niemann-Pick type C

• This disorder may or may not have manifested in the neonatal period with jaundice and splenomegaly
• Clumsiness and mild learning difficulties are common
• Decline is associated with some degree of vertical supranuclear ophthalmoplegia and often with true cataplexy, but epilepsy may be the presenting symptom
• Dysphagia is also frequently noted
• Chitotriosidase is nonspecifically increased
• Sea-blue histiocytes are often but not always seen on bone marrow examination
• and storage material may also be found in other tissues such as appendix or rectal biopsy, but if cultured fibroblasts show severely abnormal intracellular cholesterol homeostasis, then biopsy confirmation is not necessary
• Genetic confirmation by examination of NPC1 and NPC2 is possible, but is unnecessary if the fibroblast cholesterol studies are unequivocal
• When fibroblast cholesterol studies are atypical or equivocal, additional studies -biopsy, gene analysis - may be needed for secure diagnosis.

Pantothenate hinuse-associated neurodegeneration (Hallevorden-Spatz disease)

• In this disease dystonia may become extreme with gross opisthotonus
• Brain MRI eventually shows the eye of the tiger sign in the basal ganglia
• Genetic diagnosis is through PANK2.

Cerebellar leukoencephalopathy, presumed histiocytosis-related

• This regressive disorder begins with cerebellar and pyramidal and extrapyramidal features but with later behavioural difficulties and cognitive decline, and shows first on MRI as a striking cerebellar white matter signal change, followed by brainstem and basal ganglia abnormalities
• Eventually hypopituitarism may suggest histiocytosis, and sometimes biopsy will confirm this.

Subacute sclerosing panencephalitis (SSPE)

• Regression is usually gradual (but occasionally fulminant), often with behavioural change.
• School performance declines. Periodic subtle changes of expression may be apparent on close observation
• EEG usually shows periodic complexes each associated with EMG change of spasm duration
• Measles titres are elevated in blood and CSF, and CSF immunoglobulins are increased also, with oligoclonal bands

Older child and adolescent

Several of the disorders already mentioned may appear in different forms in older childhood and adolescence. Enzyme deficiencies which manifest with dysmorphism and/or visceromegaly in the very young tend to have only neurological features at later ages.Dystonia emerges as a prominent neurological sign, without specific disease implications.

Juvenile neuronal ceroid lipofuscinosis

• Visual impairment is almost always the presenting sign and because there is so little to explain the visual difficulty these affected schoolchildren may be falsely labelled with psychiatric diagnoses including 'hysterical blindness' or 'functional visual loss'.
• However, pigmentary macular changes eventually appear.
• Carefully performed ERG will show impaired retinal function from the start and in all classical cases examination of blood film will show large vacuoles (which contain fingerprint bodies on electronmicroscopy)
• In such children mutations in the gene CLN3 should be detected
• In the much less common Scottish variant with GRODs the same biochemical and genetic tests should be used as in infantile neuronal ceroid lipofuscinosis looking for a modest reduction of protein palmitoy1 thioesterase in plasma or leukocytes and mutations in CLN1.

Huntington disease

• Juvenile Huntington disease is surprisingly common, presenting with parkinsonism and on examination oculomotor apraxia in horizontal gaze, with caudate atrophy on brain MRI.
• Testing for repeats in the Huntington gene is easy, albeit tragic.

Wilson disease

• Dysarthria, subtle behavioural change and school problems, choreoathetosis and other movement disorders are some of many presentations of this rare treatable disorder
• Slit-lamp microscopy almost always shows Kayser-Fleischer rings
• Signal changes are seen in lentiform nuclei, usually with low plasma copper and copper oxidase.

Variant Creutzfeld-Jacob disease 

1. Although very rare, this has been recognized in older children. 'Psychiatric' symptoms and paraesthesiae are seen with regression, and MRI shows altered signal in the pulvinar.
2. Any CSF or other invasive studies need to be done with very special precautions against disease transmission
3. Cases in the UK and Ireland are reported to the PIND study.

Progressive myoclonus epilepsies

Unverricht-Lundborg disease

• Generalized epilepsy with tonic-clonic and clonic seizures is complicated by action myoclonus
• EEG commonly includes a photoparoxysmal response and an increased potential in response to sensory stimulation that is different to that seen in Lafora disease.
• Mutations may be found in CSTB.

Lafora disease

• This disorder also presents with adolescent convulsive epilepsy but with even more severe myoclonus, before the emergence of unsteadiness and dementia.
• Somatosensory evoked potentials are large and different in detail from those in Unverricht-Lundborg disease
• Axillary skin biopsy - or standard skin biopsy - usually but not always shows Lafora bodies.
• Mutations may not be easy to detect in EPM2A and EPM2B.

Leukodystrophies and leukoencephalopathies

• Pattern recognition is a major strategy for the identification of these white matter disorders
• In one condition or group of conditions, the eIF2B-related disorders, more than pattern recognition is often necessary.

elF2B-related disorders

• VWM (vanishing white matter) and CACH (childhood-onset ataxia with CNS hypomyelination) were earlier acronyms for eIF2B-related disorders but it has become apparent that these common autosomal recessive leukoencephalopathies have a wide phenotypic Spectrum.
• Even when brain MRI shows 'typical' features of VWM disease (T2 signal intensity of white matter equivalent to CSF, FLAIR images consistent with attenuation of involved white matter, and striae or strands in the white matter on T1), the explanation need not be a mutation in one of the five subunits of EIF2B.
• Estimation of CSF asialotransferrin is a simple way of clarifying this: if the CSF asialotransferrin is below 8% of total transferrin then it is highly likely that an EIF2B mutation will be found, if it is over 8% then EIF2B genetic testing may not be justified.

Deteriorating disorders without dementia

Friedreich ataxia

• A willowy gait with a combination of cerebellar and sensory ataxia, ocular dysmetria, absent caudal tendon reflexes and extensor plantar reflexes make the diagnosis likely
• Nerve conduction studies reveal evidence of a sensory axonal neuropathy
• Most have an abnormal echocardiogram with thick septum
• A novel MRI technique using tract-based spatial statistics and voxel-based morphometry may have wider diagnostic application
• Direct genetic testing for GAA repeats in FXN will confirm the Friedreich diagnosis.

Spinocerebellar ataxias

• A lack of symptom specificity sometimes makes it necessary to use a spinocerebellar ataxia gene test battery
• however, mitochondrial disease, especially mutations in POLG1, may cause spinocerebellar ataxia

eIF2B-related ataxia

• Because elF2B-related disorders may present with motor regression - especially progressive ataxia - without obvious cognitive problems
• Whether or not there are the well-known provocations of fever, head bump or fright, the finding of central white matter signal changes on brain MRI should prompt CSF asialotransferrin estimation as a diagnostic tool.

Progressive spastic parapareses

• A number of genetic causes of progressive or ascending spastic paraparesis are known.
• A rare treatable cause is biotinidase deficiency, detectable by direct plasma biotinidase assay
• Ascending spastic paraplegia may be due to mutations in the akin gene.

Deterioration in a child with a 'static' disorder

It is not uncommon for regression to occur from early childhood to adolescence in children with 'static' learning difficulties or apparent cerebral palsy with or without epilepsy.

Neurological investigations do not necessarily help in the situation where the cause of the disability is known, such as with deterioration in Down syndrome.

When the cause of the supposedly static disorder is unknown then it is more likely that the cause of regression will emerge through renewed neurological investigations.

For eg.

• MECP2 duplication - recurrent severe respiratory infections, slow EEG, nonspecific MRI white matter changes - multiplex ligation-dependent probe amplification.
• POLG1 mutation - deterioration is with myoclonus or epilepsy POLC1 mutation analysis
• Pyruvate dehydrogense (PDH) deficiency - often globus pallidus changes - PDH activity in fibroblasts
• GAMT deficiency - acquired movement disorder - brain or CSF H-MRS
• Organic aciduria (e.g. L-2-OH-glutaricaciduria) - white matter and dentate changes - urine organic acids
• Beware nutritional deficiencies, especially with enteral assisted feeding. 

 Further Reading

• Canafoglia L, Ciano G, Panzica F, et al. (2004) .Sensorimotor cortex excitability in Unverricht-Lundborg disease and Lafora body disease. Neurology 63: 2309-2315.
• Carrilho I, Santos M, Guimaraes A. (2008) Infantile neuroaxonal dystrophy: What's most important for the diagnosis? Eur J Paediatr Neurol 12: 491-500.
• Chedrawi AK, Ali A, Al Hassnan ZN, et al. (2008) Profound biotinidase deficiency in a child with predominantly spinal cord disease. J Child Neurol 23: 1043-1048.
• Coutelier M. Andries S, Ghariani S. (2008) Neuroserpin mutation causes electrical status epilepticus of slow-wave sleep. Neurology 71: 64-66.
• Delia Nave R, Ginestroni A, Tessa G. et al. (2008) Brain white matter tracts degeneration in Priedreich ataxia. An in vivo MRI study using tract-based spatial statistics and voxel-based morphometry. Neuroimage 40: 19-25.
• Eymard-Pierre E, Lesca G, Dollet S, et al. (2002) Infantile onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am J Hum Genet 71: 518-527.
• Finsterer J. (2008) Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol 39: 223-235.
• Gregory A, Westaway SK, Holm IE. (2008) Neurodegeneration associated with genetic defects in phospholipase A(2). Neurology 71: 1402-1409.
• Kalviainen R, Eriksson K, Losekoot M. et al. (2007) Juvenile-onset neuronal ceroid lipofuscinosis with infantile GI.N1 mutation and palmitoyl-protein thioesterase deficiency, Eur J Neurol 14: 367-372.
• Kurian MA. Morgan NV, MacPherson L, et al. (2008) Phenolypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN). Neurology 70: 1623-1629.
• Maegawa GHB, Stockley T, Tropak M, et al. (2006) The natural history of juvenile or subacute GM2 gangliosidosis: 21 new cases and literature review of 134 previously reported. Pediatrics 118: 1550-1560. Miller RJ, Roos RP. (2000) What happens when mutant neuroserpins get into bad shape. Lancet 355: 590-591.
• Prashanth LK, Taly AB. Sinha S, Ravi V. (2007) Subacute sclerosing panencephalitis (SSPE): an insight into the diagnostic errors from a tertiary care university hospital. J Child Neurol 22: 683-688.
• Roberts EA, Schilsky ML. (2008) Diagnosis and treatment of Wilson disease: an update. Hepatolog)' 47: 2089-2111.
• Schiffmann R, van der Knaap MS. (2009) Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 72: 750-759.
• Shahwan A, Parrell M, Delanty N. (2005) Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol 4: 239-248.
• Soltanzadeh A, Soltanzadeh P. Nafissi S. et al. (2007) Wilson's disease: a great masquerader. Bur Neurol 57: 80-85.
• van der Knaap MS, Arts WF, Garbern JY, el al. (2008) Cerebellar leukoencephalopathy most likely histiocylosis-relatecl. Neurology 71: 1361-1367.
• van der Knapp MS, Valk J. (2005) Magnetic Resonance of Myelinntion and Myelin Disorder.-,, 3rd edn. Berlin Heidelberg, New York: Springer.
• Vanderver A, Hathout Y. Maletkovic J, et al. (2008) Sensitivity and specificity of decreased CSF asialotransferrin for eIF2B related disorder. Neurology 70: 2226-2232.
• Velinov M, Zellers N, Styles J. el al. (2007) Homozygosity for mutation G212A of the gene for aspanoacylase is associated with atypical form of Canavan's disease. Clin Genet 73: 288-289.
• Walker RH, Jung HH, Dobson-Stone C, el al. (2007) Neurologic phenotypes associated with acanthocytosis. Neurology 68: 92-98.
• Source:
  Mary D. King, 2009. A Handbook of Neurological Investigations in Children. 1 Edition. Mac Keith Press.