Symptoms » Learning disabilities » Book Sections

Developmental Delay

Definedas disturbance in acquisition of motor, language, and/orcognitive skills.

When disturbance involves ≥2 ofthese domains, global developmental delay (children <5yrs of age) or mental retardation (individuals >5 yrs ofage and IQ <70) usually exists. Global delay may be dueto static or progressive disorder of CNS, but overlap can occurbetween these 2 categories.

Children with static disorder may deterioratein function due to worsening spasticity or contracture developmentduring growth spurts or periods of inadequate therapy. Cognitivefunction may deteriorate in static conditions due to untreated orundertreated epilepsy or unrecognized attentional or emotional orpsychiatric factors. Children with degenerative disorder may havestatic course until regression occurs with oxidative stress (e.g.,infection or surgery).

Principal Causes of Developmental Delay

1. Grossmotor delay
   1. Cerebralpalsy
   2. Neuromuscular disorders
2. Delayed or impaired language
   1. Impairedhearing
   2. Receptive and expressive language disorders
   3. Pervasive developmental disorders
3. Static global delay
   1. Chromosomaldisturbances
   2. Maternal or infant undernutrition
   3. Maternal drug or alcohol use
   4. Cerebral malformation
   5. Hypoxic-ischemic encephalopathy
   6. Intracranial hemorrhage
   7. Infection
   8. Brain tumor
   9. Cerebrovascular disorders
   10. Psychologic disturbances
   11. Unknown
4. Progressive global delay
   1. Neurocutaneousdisorders
      1. Tuberoussclerosis
      2. Neurofibromatosis
   2. Metabolic brain disorders
      1. Diseasesprimarily affecting gray matter (without visceral storage)
         1. GM-2 gangliosidosis(Tay-Sachs disease)
         2. Neuronal ceroid lipofuscinoses
         3. Alpers disease
         4. Menkes disease
         5. Rett syndrome
      2. Diseases primarily affecting gray matter(with visceral storage)
         1. GM-1 gangliosidosis
         2. GM-2 gangliosidosis (Sandhoff disease)
         3. Niemann-Pick disease
         4. Gaucher disease
         5. Fucosidosis
         6. Sialidosis type II
      3. Diseases primarily affecting whitematter
         1. Galactosemia
         2. Phenylketonuria
         3. Maple syrup urine disease (intermediate)
         4. Homocystinuria
         5. Urea cycle defects
         6. Canavan disease
         7. Alexander disease
         8. Globoid leukodystrophy (Krabbe disease)
         9. Pelizaeus-Merzbacher disease
         10. Metachromatic leukodystrophy
      4. Diseases affecting both gray and whitematter
         1. Mucopolysaccharidoses
            1. Mucopolysaccharidosistype I (Hurler disease)
            2. Mucopolysaccharidosis type II (Hunterdisease)
            3. Mucopolysaccharidosis type III (Sanfilippodisease)
            4. Mucopolysaccharidosis type VII (Slydisease)
         2. Mitochondrial disorders
         3. Peroxisomal disorders
      5. Miscellaneous
         1. Lesch-Nyhan syndrome
   3. Congenital hypothyroidism
   4. Human immunodeficiency virus infection

Clinical Features and Diagnosis

Gross Motor Delay

Cerebral Palsy

Nonprogressivedisorder of brain affecting movement and posture.

Causes include prematurity with periventricularleukomalacia, perinatal asphyxia, head trauma, and unknown etiologies.

Characteristic features are delayedmotor skills and abnormalities of muscle tone. Most common typeis characterized by spasticity, hypertonia, and abnormal postures.

Significant involvement of both armsand legs is called quadriplegia. Involvement of legs more than armsis known as diplegia, whereas extremity involvement on one sideof the body is termed hemiplegia.

Choreoathetosis and ataxia occur inless common types. Delays in cognitive, language, and social developmentalso may occur.

Neuromuscular Disorders

Includedisorders of anterior horn cell, peripheral nerve, neuromuscularjunction, and muscle.

Characteristic findings include hypotoniaand weakness, which lead to delayed acquisition of motor skills.

Cognitive development is usually normalbut may be impaired in some disorders.

See Chap.33, Hypotonia and Weakness.

Delayed or Impaired Language

Delay in language development may be isolatedfinding and occur without delay in acquisition of motor skills.However, because language reflects cognitive ability, it often signalspresence of global delay.

Impaired Hearing

In any childwith impaired language development, important to determine whether hearingis normal.

See Chap.26, Hearing Loss and Deafness.

Receptive and Expressive Language Disorders

Some childrenwith normal hearing and cognitive ability may have delay in receptive orexpressive language skills. Taking longer to respond to questionsor instructions and experiencing problems in task completion mayindicate difficulty in understanding what was said. Children withnormal hearing, cognition, and receptive language may have expressivelanguage delay where gestures are used for communication.

See Chap.72, Verbal Communication Difficulty.

Pervasive Developmental Disorders

Autisticdisorder, the most common pervasive developmental disorder, is characterizedby impaired language development, abnormal personal-social interactions,and unusual repetitive behaviors.

Children with other types of pervasivedevelopmental disorder do not meet criteria for autistic disorderbut have impaired social interaction and communication skills andunusual stereotypic repetitive behaviors.

See Chap.57, School Underachievement and Academic Failure.

Static Global Delay

Chromosomal Disturbances

Most commonchromosomal disorder is trisomy 21.

>90% of affected childrenhave nontranslocation trisomy 21, and remainder have translocationsor mosaic situations.

Clinical findings include round face,depressed nasal bridge, upslanting palpebral fissures, epicanthalfolds, speckling of iris, excess skin on nape of neck, angulationand overfolding of upper helix of ears, hypermobility of joints,hypoplasia of midphalanx of fifth finger with clinodactyly, simiancrease, and hypotonia.

Congenital heart disease (most commonlyVSD, AV canal defect, ASD) occurs in about 50%. Mild-to-moderatemental retardation occurs in most individuals.

Diagnosis is confirmed by chromosomalkaryotype.

Another common chromosomal disorderassociated with developmental delay is fragile X syndrome.

Fragile site(constriction) exists at Xq27 locus. Mutations of FMR1 gene at thislocus have been found to cause this disorder.

Clinical findings include prominentforehead, large ears, macrocephaly, hyperextensible joints, andlarge testes in pubertal males. Female carriers may have normalintelligence or mild mental retardation.

Molecular genetic analysis is diagnostic.

Other chromosomal disorders may beassociated with developmental delay.

Include Prader-Willi syndrome, Turner syndrome,Klinefelter syndrome, autosomal syndromes (trisomies 13, 18), deletionsyndromes (chromosomes 4, 5, 13, 18), aneuploidy syndromes (trisomies4p, 5p, 8 mosaic, 9p, 10q), and sex chromosomal syndromes (XYY,XXX, XXXX, XXXXX).

Chromosomal karyotype is diagnostic.

Maternal or Infant Undernutrition

Any causeof severe maternal or infant undernutrition may cause disturbanceof CNS development, with smaller head size reflecting decreasedbrain growth.

Duration and timing of undernutritionare important factors in development of cognitive defects. In youngchildren, starvation over considerable period has been shown toaffect intelligence and behavior.

Maternal Drug or Alcohol Use

Use of cocaine,alcohol, and some pharmacologic agents by mother during pregnancy maycause serious disturbances in development of nervous system of fetus.

Cocaine can produce cerebral hemorrhageand infarction, which may contribute to subsequent cognitive deficits.

Excessive alcohol ingestion is responsiblefor fetal alcohol syndrome, whose manifestations include dysmorphiccraniofacial features (microcephaly, short palpebral fissures, flattenedmidface, poorly developed philtrum, thin upper lip), brain dysfunction(poor memory, difficulty processing information, hyperactivity),and impaired intrauterine and postnatal growth.

Use of anticonvulsants (e.g., phenytoin,valproic acid, and carbamazepine) has been associated with cerebralmalformations and developmental delay.

Cerebral Malformation

Should besuspected in any child with developmental delay who is dysmorphic,has other organ malformations, or who has abnormal size or shapeof head.

CT or MRI is diagnostic.

Hypoxic-Ischemic Encephalopathy

May causemotor and cognitive defects as well as seizures.

Principal cause in newborns is perinatalasphyxia, whereas common causes in infants and children includeupper airway obstruction (foreign body, trauma), pulmonary disease(near drowning, inhalation injury), cardiovascular disease (shockof any cause), neurologic disorders (head trauma, status epilepticus,meningitis, encephalitis), intoxications (carbon monoxide), andmetabolic disorders.

CT or MRI may help delineate extentof brain injury.

Intracranial Hemorrhage

Preterminfants who have had significant intraventricular hemorrhage mayhave developmental delay.

Likelihood of hemorrhage increasesas gestational age decreases.

Another cause of intracranial hemorrhagein infants and children is head trauma (accidental or nonaccidental).Sequelae of significant head trauma include impaired cognition,learning difficulties, motor disturbances, vision and hearing deficits,disorders of speech and language, posttraumatic epilepsy, and emotionalproblems.

See Chap.3, Alteration in Consciousness.

Infection

Congenitalinfections that may produce developmental delay include rubellavirus, cytomegalovirus, herpes simplex virus, toxoplasmosis, andsyphilis. See Chap. 36, Jaundice.

Bacterial meningitis may produce cerebritis,cerebral infarction, and brain necrosis. Among the sequelae areseizures, impaired motor and cognitive function, hydrocephalus,deafness, blindness, and learning disabilities.

Certain viruses (e.g., herpes simplexvirus) cause infection of neuronal cells and hemorrhagic necrosisof the brain.

Sequelae of herpes virus encephalitisinclude seizures, language dysfunction, and motor and cognitivedeficits.

Brain Tumor

Variousbrain tumors may lead to intellectual and motor deficits due toinitial location of tumor and subsequent treatment, including surgery,chemotherapy, and radiation.

See Chap.25, Headache.

Cerebrovascular Disorders

Thrombosis,embolism, or hemorrhage may cause cerebral infarction.

Common sequelae include hemiparesis,speech defects, seizures, behavioral problems, and learning disabilities.

See Chap.3, Alteration in Consciousness.

Psychologic Disturbances

Neglectand deprivation, severe depression, and psychoses can lead to developmental delayand decrease in cognitive function.

See Chap.57, School Underachievement and Academic Failure.

Unknown

In many cases the reason for developmentaldelay or mental retardation in child is unknown.

Progressive Global Delay

Neurocutaneous Disorders

Tuberous Sclerosis

Autosomal-dominantdisorder with variable expression. 2 gene loci have been mapped:chromosome 9q34 and chromosome 16p13.3.

Revised diagnostic criteria have beenproposed by Roach et al. (1998). Definitive diagnosis requires 2major features or 1 major feature and 2 minor features.

Major features include facial angiofibromasor forehead plaque, nontraumatic ungual or periungual fibroma, ≥3hypomelanotic macules, shagreen patch, multiple retinal nodularhamartomas, cortical tuber, subependymal nodule, subependymal giantcell astrocytoma, single or multiple cardiac rhabdomyomas, lymphangiomyomatosis,and renal angiomyolipoma.

Minor features include multiple randomlydistributed pits in dental enamel, hamartomatous rectal polyps,bone cysts, cerebral white matter daily migration lines, gingivalfibromas, nonrenal hamartoma, retinal achromic patch, "confetti" skinlesions, and multiple renal cysts.

Neurofibromatosis

Autosomal-dominantdisorder has 2 types: peripheral (type 1) and central (type 2).

Gene locus for type 1 is chromosome17q11, whereas locus for type 2 is chromosome 22q12.

Diagnostic criteria for type 1 include≥2 findings: ≥6 café au lait macules that are >5mm in diameter in children and >15 mm in diameter in adolescents;freckling in the axillary or inguinal regions; ≥2 neurofibromasof any type or 1 plexiform neurofibroma; bilateral optic nerve gliomas; ≥2iris Lisch nodules on slit-lamp exam; distinctive osseous lesions(e.g., sphenoid wing dysplasia or congenital bowing or thinningof cortex of long bones with or without pseudoarthrosis); and first-degree relative(parent, sibling, or offspring) with type 1 by these same criteria.

Diagnostic criteria for type 2 includebilateral eighth nerve masses seen with appropriate imaging techniques,or first-degree relative with type 2 and either unilateral eighthnerve mass or 2 of the following: neurofibroma, meningioma, glioma,schwannoma, and juvenile posterior subcapsular lenticular opacity.

Metabolic Brain Disorders

May be generallydivided into 3 groups: those that primarily affect gray matter,those that primarily affect white matter, and those that affectboth gray and white matter.

Gray matter diseases may be furthercategorized by presence or absence of visceral storage (hepatosplenomegaly).Initially, gray matter diseases are characterized by seizures, failureof cognitive development, retinal disease, myoclonus, and spikesor sharp waves on the electroencephalogram.

White matter diseases are characterizedby marked motor deficits, including spasticity and slow encephalographicactivity.

Important to recognize that considerableoverlap may occur between gray and white matter disorders, particularlylater in disease course.

Diseases Primarily Affecting Gray Matter (without VisceralStorage)

GM-2 Gangliosidosis (Tay-Sachs Disease)

Autosomal-recessivedisease caused by deficiency in activity of hexosaminidase A, whosegene locus has been mapped to chromosome 15.

Typical onset is between 3 and 6 mosof age, with abnormal startle reaction to noise or light and developmentaldelay.

Cherry red macular spot is seen inalmost all cases. Spasticity and dementia usually occur by 1 yrof age. Seizures and macrocephaly develop during second yr, andmost die by school age.

Juvenile form is caused by partialdeficiency of hexosaminidase A. Children appear normal until aboutage 3, when they develop speech and language problems and gait disturbance,characterized initially by ataxia, and later by spasticity. Dementiafollows, and in some cases seizures occur.

Decreased hexosaminidase A activityin leukocytes or cultured fibroblasts confirms diagnosis.

Neuronal Ceroid Lipofuscinoses

Characterizedby accumulation of ceroid and lipofuscin lipopigments in brain,retina, and some visceral tissues. Abnormal genes have been identifiedfor each of type.

Classification is based on age of onset.Regardless of age of onset, developmental regression almost alwaysoccurs.

Onset of infantile type is usually6–12 mos of age, with visual loss and myoclonus followed byhypotonia and psychomotor regression.

Late-infantile type has its onset between2 and 3 yrs of age with seizures and visual loss followed by developmentalarrest, ataxia, and dementia.

Early-juvenile type presents between4 and 5 yrs of age, with visual loss followed by seizures and dementiabetween 5 and 10 yrs of age.

In late-juvenile type, onset is between5 and 10 yrs of age, with visual loss followed by poor school performanceand behavioral disturbances indicative of dementia.

Electron microscopy of conjunctivalepithelium, skin, or leukocytes shows typical lipopigment inclusions.

Alpers Disease

Combinationof gray matter neuronal degeneration and liver failure is hallmarkof this autosomal-recessive disorder.

Onset is during first year of life,with developmental delay, seizures, and failure to thrive. Neurologicregression with impaired vision and hearing follow.

CT and MRI show marked brain atrophy.

Menkes Disease

X-linkedrecessive disorder caused by mutations in ATP7A gene, which affectsintestinal transport of copper.

Onset is usually by 3 mos of age withmyoclonic seizures and developmental delay. Sparse, wiry, or kinkyscalp hair (pili torti) is characteristic. Serum copper and ceruloplasminlevels are low. Molecular genetic analysis is definitive.

Rett Syndrome

Caused bymutations in gene at Xq28 that encodes for methyl-CpG-binding protein-2(MECP-2). Appears to occur exclusively in females.

Although development is normal forfirst 6–18 mos of age, arrested development follows withloss of language skills, decreased head growth leading to microcephaly,and diminished purposeful use of hands. Seizures, ataxia, spasticity,and stereotypic hand-washing or hand-wringing movements characterizeclinical course.

Molecular genetic analysis is definitive.

Diseases Primarily Affecting Gray Matter (with Visceral Storage)

GM-1 Gangliosidosis

Autosomal-recessivedisorder caused by deficiency in activity of beta-galactosidase, whosegene locus has been mapped to chromosome 3p.

Onset of type I is between 6 and 18mos of age.

Characteristic Hurler phenotype withcoarse facies, hepatosplenomegaly, and dysostosis multiplex occursalong with seizures, spasticity, and psychomotor delay. Macularcherry red spot is found in about 50%. Neurologic deteriorationfollows with development of deafness and blindness.

Onset of type II is between 1 and 2yrs of age, with seizures, spasticity, ataxia, loss of speech, andneurologic regression.

Onset of type III is usually in childhoodor adolescence, with difficulty in speech, extrapyramidal signs(e.g., dystonia), often mildly impaired intellectual function, andoccasional seizures.

Coarse facies, hepatosplenomegaly,and cherry red macular spot do not occur in types II and III.

Enzyme assay of leukocytes or culturedfibroblasts is diagnostic.

GM-2 Gangliosidosis (Sandhoff Disease)

Autosomal-recessivedisorder caused by deficiency in activity of hexoaminidases A andB. Gene locus of hexosaminidase A is on chromosome 15, whereas locusfor hexosaminidase B is on chromosome 5.

Clinical findings are similar to Tay-Sachsdisease, except that hepatosplenomegaly and mild dysostosis multiplexalso occur.

Decreased activity of hexoaminidasesA and B in serum, leukocytes, or cultured fibroblasts is diagnostic.

Niemann-Pick Disease

Types Aand B are caused by deficiency in activity of sphingomyelinase,whose gene locus has been mapped to chromosome 11p15.

In type A,sphingomyelin accumulates in all tissues, including brain. Onsetis in infancy with feeding difficulty, failure to thrive, hepatosplenomegaly,and psychomotor regression. Cherry red macular spot can be seenin about 50% of cases. Vacuolated lymphocytes may be seenin peripheral blood, whereas vacuolated histiocytes may be seenin bone marrow.

In type B, sphingomyelin accumulationproduces hepatosplenomegaly without CNS involvement (discussed herefor comparison with other types).

In both types, enzyme assay of leukocytesor cultured fibroblasts is diagnostic.

Type C is caused by defect in cholesterolesterification that leads to secondary deficiency in sphingomyelinaseactivity. Gene locus has been mapped to chromosome 18q11-12.

Early-onsetform usually occurs after age 2, with hepatosplenomegaly and developmentaldelay followed by ataxia and dementia.

Delayed-onset form begins in childhoodwith dystonia or cerebellar ataxia. Apraxia of vertical gaze, seizures,spasticity, and dementia follow.

Late-onset form begins in adolescencewith a clinical picture similar to that of delayed-onset form, exceptthat progression is slower.

Demonstration of impaired cholesterolesterification is diagnostic.

Gaucher Disease

Deficiencyin activity of glucocerebrosidase (beta-glucosidase) results inaccumulation of glucocerebroside (glucosylceramide). Gene has beenmapped to chromosome 1q21.

Type I does not affect nervous systembut is included in this discussion for comparison with other types.Principal finding is hepatosplenomegaly. Anemia, thrombocytopenia,and neutropenia secondary to hypersplenism also may occur.

Type II usually presents by 6 mos ofage with difficulty in sucking and swallowing, hepatosplenomegaly,spasticity, and psychomotor deterioration.

Onset of type III is in childhood witha slower progression compared with type II. Hepatosplenomegaly usuallyprecedes neurologic abnormalities, which include seizures, spasticity,ataxia, cranial nerve dysfunction, and dementia.

Presence of Gaucher cells (histiocytes)in bone marrow is virtually diagnostic. Enzyme assay of leukocytesor cultured fibroblasts is confirmatory.

Fucosidosis

Caused bydeficiency in activity of alpha-L-fucosidase, whose gene locus ischromosome 1p34.

These children have some of featuresof mucopolysaccharidosis (MPS) (e.g., coarse facies, hepatomegaly,and dysostosis multiplex).

In type I, psychomotor delay occursduring first year of life, with subsequent neurologic deterioration.Type II is characterized by onset during childhood with slower neurologicprogression, whereas type III, although clinically similar to typeII, has its onset after age 10.

Lab findings include excessive amountof fucose-containing oligosaccharides in urine and increased amountof sodium and chloride in sweat.

Enzyme assay of leukocytes or culturedfibroblasts is diagnostic.

Sialidosis Type II

Caused bydeficiency of glycoprotein-specific alpha-neuraminidase activity.

Onset is variable. Can appear at birthor not until second decade of life.

Clinical manifestations include mildhepatosplenomegaly, joint contractures, cherry red macular spot,and slow intellectual deterioration. Hypotonia and ataxia are variablefindings.

Diagnosis is confirmed by enzyme assayof leukocytes or cultured fibroblasts.

Diseases Primarily Affecting White Matter

Galactosemia

Classicform—galactose-1-phosphate uridyltransferase deficiency—cancause developmental delay and mental retardation.

See Chap.36, Jaundice.

Phenylketonuria

Classicform caused by deficiency in activity of phenylalanine hydroxylase,which converts phenylalanine to tyrosine. Gene locus has been mappedto chromosome 12q24.1. Neonatal screening can detect this disorder.Quantitative phenylalanine levels are diagnostic.

Typical clinical findings are fairhair and blue eyes, eczema, musty odor, and seizures.

Treatment with phenylalanine-free dietas soon as possible after birth can prevent neurologic sequelae.

Failure to diagnose this disorder inearly infancy and lack of proper treatment lead to developmentaldelay and mental retardation.

Maple Syrup Urine Disease (Intermediate)

Classicand intermittent forms are associated with acute encephalopathyand ketoacidosis, whereas intermediate form has its onset in lateinfancy and is associated with failure to thrive, ataxia, and developmentaldelay.

Urine has odor of maple syrup.

Serum concentrations of isoleucine,valine, and leucine are increased, but not as high as in classicform.

See Chap.3, Alteration in Consciousness.

Homocystinuria

Deficiencyin activity of cystathionine beta-synthase is most common causeof homocystinuria. Gene locus has been mapped to chromosome 21q22.

Clinical findings include developmentaldelay, lens dislocation (typical onset from 2 to 10 yrs of age),osteoporosis (older children), and cerebral thromboembolism.

Newborn screening detects increasedlevels of methionine in blood.

Increased serum concentrations of homocystineand methionine are diagnostic, whereas enzyme assay of culturedfibroblasts or liver is confirmatory.

Dietary treatment consisting of methioninerestriction and cystine supplementation can prevent mental retardationif begun soon after birth.

Urea Cycle Defects

Conversionof ammonia to urea is controlled by 6 enzymes: carbamyl phosphatesynthetase, N-acetylglutamate synthetase, ornithine transcarbamylase,argininosuccinic acid synthetase, argininosuccinic acid lyase, andarginase.

Deficiency in activity of any of theseenzymes can lead to hyperammonemia, which can result in subsequentneurologic dysfunction, including developmental delay and psychomotorretardation.

See Chap.3, Alteration in Consciousness.

Canavan Disease

Autosomal-recessivedisorder caused by deficiency in activity of aspartoacylase, whosegene locus has been mapped to chromosome 17pter-p13.

Most prominent pathologic finding isspongy degeneration of white matter. Onset is in early infancy,with irritability and poor visual fixation. Course is characterizedby hypotonia followed by spasticity; characteristic posture consistingof arm flexion, hyperextension of legs, and head retraction; macrocephaly;optic atrophy; and psychomotor regression.

Large increase in urinary level ofN-acetylaspartic acid is diagnostic. Enzyme assay in cultured fibroblastsis confirmatory.

Alexander Disease

Mutationsin 2 genes have been implicated in the cause of this disorder. 1locus has been mapped to chromosome 17q21 and the other to chromosome11q13.

Usual onset is in infancy, with developmentalarrest, spasticity, macrocephaly, and seizures.

MRI demonstrates involvement of deepwhite matter.

Diagnosis is usually based on clinicaland radiologic findings. Brain biopsy that reveals presence of Rosenthalfibers in cytoplasm of astrocytes is definitive.

Globoid Leukodystrophy (Krabbe Disease)

Autosomal-recessivedisorder caused by deficiency in activity of galactosylceramide beta-galactosidase,whose gene locus has been mapped to chromosome 14q31.

Onset is usually in early infancy,with irritability, hypersensitivity to stimulation, progressiveincrease in muscle tone, and developmental regression.

MRI shows demyelinization of cerebralhemispheres. Spinal fluid protein is increased, and motor nerveconduction velocity is slow.

Diagnosis is confirmed by enzyme assayof leukocytes or cultured fibroblasts.

Pelizaeus-Merzbacher Disease

Classicform of this X-linked disorder is caused by deficiency of proteolipidprotein, a constituent of myelin. Gene has been mapped to Xq22 locus.

Onset is usually in early infancy,with head nodding and pendular nystagmus followed by spasticityand arrest of psychomotor development. Seizures and optic atrophyalso occur.

MRI shows demyelinization of cerebralhemispheres.

Molecular genetic analysis confirmsdiagnosis.

Metachromatic Leukodystrophy

Autosomal-recessivedisorder caused by deficiency in activity of arylsulfatase A, whosegene locus is on chromosome 22.

Onset in infancy is usually between1 and 2 yrs of age, with gait disturbance and spasticity. Loss ofspeech, cranial nerve dysfunction, optic atrophy, weakness, andintellectual deterioration follow.

Onset of juvenile form is usually betweenages 5 and 10, with speech disturbance, ataxia, and impaired intellectualperformance.

Adult form occurs after age 16, withintellectual and behavioral disturbances followed by movement andposture abnormalities.

MRI shows demyelinization of cerebralhemispheres.

Enzyme assay of leukocytes or culturedfibroblasts is confirmatory.

Diseases Affecting Both Gray and White Matter

Mucopolysaccharidoses (MPSs)

Group ofdisorders caused by deficiency in activity of specific lysosomalenzymes responsible for degradation of mucopolysaccharides. Genetictransmission is autosomal-recessive, except for type II, which isX-linked.

Characteristic findings include coarsefacial features, hepatosplenomegaly, and dysostosis multiplex. Cornealclouding occurs in all types except types II and III. Intellectualdysfunction is feature of types I, II, III, and VII. Excessive amountsof different mucopolysaccharides are found in urine.

Diagnosis is confirmed by specificenzyme assay of leukocytes or cultured fibroblasts.

Mucopolysaccharidosis Type I (Hurler Disease)

MPS typeI (Hurler disease) is prototype for all MPSs and is caused by deficiencyin activity of alpha-L-iduronidase, whose gene has been mapped tochromosome 4p16.3.

Clinical findings include coarse facialfeatures, joint contractures, hepatosplenomegaly, decreased lineargrowth, macrocephaly, hearing loss, cloudy corneas, kyphoscoliosis,dysostosis multiplex, and developmental delay. Loss of cognitiveskills occurs over time. Excessive amount of dermatan sulfate andheparan sulfate is found in urine.

Mucopolysaccharidosis Type II (Hunter Disease)

Caused bydeficiency in activity of iduronate-2-sulfatase, whose gene locushas been mapped to chromosome X28.

Clinical findings are similar to thosefor MPS I but less severe. Neurologic regression is slowly progressive.Excess of dermatan sulfate and heparan sulfate is found in urine.

Mucopolysaccharidosis Type III (Sanfilippo Disease)

4 recognizedtypes of MPS III have similar clinical presentation and can onlybe distinguished biochemically. Each type is characterized by deficiencyin activity of specific enzyme involved in degradation of heparansulfate: MPS III-A (heparan-N-sulfatase deficiency); MPS III-B (alpha-N-acetylglucosaminidasedeficiency); MPS III-C (acetyl-CoA: alpha-glucosaminide N-acetyltransferase deficiency); and MPS III-D (N-acetylglucosamine-6-sulfatasedeficiency). Gene loci have been mapped to different chromosomes.

Primarily neurologic disorder withdevelopmental delay in infancy and mental deterioration in childhood.Somatic and skeletal abnormalities are mild.

In all types, excessive amount of heparansulfate is excreted in urine. Specific enzyme assays using leukocytesor cultured fibroblasts distinguish different types.

Mucopolysaccharidosis Type VII (Sly Disease)

Caused bydeficiency in activity of beta-glucuronidase, whose gene locus hasbeen mapped to chromosome 7q21.11.

Clinical features are similar to thosefor MPS I. Psychomotor retardation develops after 2 yrs of age butnot in all cases. Urinary excretion of heparan sulfate, dermatansulfate, and chondroitin 4,6-sulfate is excessive.

Mitochondrial Disorders

Leigh syndromeis prototype mitochondrial disorder that causes progressive deteriorationof neurologic function.

Onset is usually in infancy or earlychildhood but can occur in neonatal period. Characteristic featuresinclude poor feeding, episodes of hypoventilation or apnea, seizures,hypotonia, weakness, cranial nerve dysfunction, disorders of movement(e.g., dystonia), and developmental arrest followed by regression.Lactate level in CSF is usually increased, but serum lactate/pyruvateratio may or may not be increased.

Several biochemical defects have beenassociated with this disease, including complex I (NADH-coenzymeQ reductase), complex IV (cytochrome-c oxidase), complex V (ATPasesubunit 6), and pyruvate dehydrogenase complex.

Diagnosis is based on clinical andMRI findings, and skin fibroblast culture or muscle biopsy findings,including respiratory chain enzyme analysis.

Peroxisomal Disorders

Zellwegersyndrome is prototype peroxisomal disorder in which there is decreasein number or structure of peroxisomes.

Caused by mutations in several genes involvedin peroxisome biogenesis.

Characteristic findings are typicalfacies (prominent forehead, epicanthal folds, low nasal bridge,anteverted nostrils, narrow upper lip), hepatomegaly, seizures,hypotonia, renal cysts, patellar stippled calcifications, visualproblems (cataract, optic nerve hypoplasia, glaucoma), and lackof psychomotor development.

Diagnosis is based on clinical featuresand evidence of decreased peroxisomal function (e.g., increasedserum levels of very-long-chain fatty acids, pipecolic acid, andbile acid intermediates) and deficiency of plasmalogens in RBCs.

X-linked adrenoleukodystrophy (ALD)is prototype disorder of single peroxisomal enzyme with normal peroxisomalnumber and structure.

Caused by deficiency in activity of a peroxisomalmembrane protein, ALDP. Gene locus has been mapped to Xq28.

Onset is usually between 5 and 10 yrsof age, with learning problems in school, impaired vision, adrenalinsufficiency, and neurologic deterioration.

Diagnosis is confirmed by presenceof increased amounts of very-long-chain fatty acids in plasma, leukocytes,erythrocytes, or cultured fibroblasts.

Miscellaneous: Lesch-Nyhan Syndrome

Caused bydeficiency in activity of hypoxanthine-guanine phosphoribosyl transferase,which leads to overproduction of uric acid.

Onset is between 3 and 6 mos of age,with psychomotor delay followed by choreoathetosis. Most strikingfeature is compulsive self-mutilation with biting of fingers andlips, which usually occurs between 2 and 4 yrs of age. Serum uricacid concentration is increased.

Enzyme assay using erythrocytes orcultured fibroblasts is confirmatory.

Congenital Hypothyroidism

May causedevelopmental delay and ultimately mental retardation, so importantthat proper treatment follow prompt diagnosis. Newborn screeningdiagnoses virtually all cases.

Clinical findings usually appear inneonatal period and include jaundice, constipation, umbilical hernia,and large posterior fontanelle.

Low serum T4 and high serum TSH levelsconfirm diagnosis.

See Chap.23, Growth Deficiency: Weight and Height.

HIV Infection

Neurologicmanifestations of this retroviral infection include seizures, spasticity, ataxia,involuntary movements, cranial nerve dysfunction, development regression,and eventually dementia.

See Chap.53, Recurrent Infection.

Diagnostic Approach

Cornerstoneof evaluation for developmental delay or mental retardation is thorough historyand physical exam, including neurologic exam. First step is to determinewhether delay involves motor or language skills alone or whetherglobal delay exists. If delay is global, next step is to determine whetherit is static or progressive. Final step is to make specific diagnosis,if possible. This is important for management, prognosis, and geneticcounseling purposes.

Presence of specific physical, radiologic,and lab findings helps narrow diagnostic possibilities when consideringmany metabolic brain diseases associated with developmental delayor loss of attained skills (Table13.1 ). Children with more severe handicap (IQ <40)are more likely to have specific identifiable disorder.

Precise cause of mild developmentaldelay cannot be determined in most cases.

Table 13.1. Physical, Radiologic, and Lab Findings in Some DisordersAssociated with Developmental Delay

Skin changes
Adenoma sebaceum	Tuberous sclerosis
Café au lait spots	Neurofibromatosis
Increased pigmentation	Adrenoleukodystrophy
Friable, kinky hair	Menkes syndrome
Macrocephaly without hydrocephalus	Alexander disease
	Canavan disease
	Tay-Sachs disease (some cases)
Dysostosis multiplex	Mucopolysaccharidoses
	GM-1 gangliosidosis
Abnormal urinary or body odors
Maple syrup	Maple syrup urine disease
Musty	Phenylketonuria
Hepatomegaly or hepatosplenomegaly	Gaucher disease
	Mucopolysaccharidoses
	GM-1 gangliosidosis
	Sandhoff disease
	Niemann-Pick disease
	Fucosidosis
Dysmorphic or coarse facial features	Mucopolysaccharidoses
	GM-1 gangliosidosis
	Fucosidosis
	Zellweger syndrome
Ocular findings
Corneal opacification	Mucopolysaccharidoses
	GM-1 gangliosidosis
Cataracts	Galactosemia
	Rubella (congenital)
	Zellweger syndrome
Roving or dancing eye movements	Pelizaeus-Merzbacher disease
Macular cherry red spot	GM-1 gangliosidosis
	Tay-Sachs disease
	Sandhoff disease
	Niemann-Pick disease (types A and C)
	Sialidosis type II
Optic atrophy and blindness	Metachromatic leukodystrophy
	Globoid cell leukodystrophy
	Canavan disease
	Neuronal ceroid lipofuscinosis
	Leigh syndrome
	Zellweger syndrome
Lens dislocation	Homocystinuria
Neurologic findings
Brain lesions and peripheral nerve involvement (hypotonia, weakness, areflexia, sensory loss)	Metachromatic leukodystrophy
	Globoid cell leukodystrophy
Absent deep tendon reflexes with Babinski sign	Metachromatic leukodystrophy (beyond infancy)
Marked rigidity, opisthotonus, and tonic spasms	Gaucher disease (infantile)
	Globoid cell leukodystrophy

Developmental Testing

Denver DevelopmentalScreening Test II can screen for developmental delay in childrenup to 5 yrs of age.

Clinical Linguistic and Auditory MilestonesScale (CLAMS) can be used in office settings for language assessmentin children up to 3 yrs of age.

Clinical Adaptive Test supplementsCLAMS test and measures fine motor, adaptive, and visual perceptiveskills in children who are also <3 yrs of age.

Intelligence Testing

Child withsuspected cognitive delay or mental retardation should have intelligence testing.IQ can be used to categorize degree of retardation.

IQ of 55–70 is mild, 40–55is moderate, and <40 is severe.

Bayley Scales of Infant Developmentare used in children <2.5 yrs of age. Stanford-Binet IntelligenceScale is used to test children >2 yrs of age. WechslerScales can be used to test preschool and school-aged children, aswell as adolescents.

Adaptive Testing

Adaptive skills need to be assessed. Thiscan be done with Vineland Adaptive Behavior Scales, Woodcock-JohnsonScales of Independent Behavior, or American Association of MentalDeficiency Adaptive Behavior Scales. By means of parent interviews,these tests help assess self-help skills, judgment, interactionand cooperation with others, and difficult behaviors.

Diagnostic Tests

Because children with developmental delayor mental retardation may have definable cause that can have implicationsfor treatment, prognosis, and genetic counseling, diagnostic testingis necessary. Selected investigations offer best chance of makingspecific diagnosis.

Genetic Testing

Chromosomaldisorders are common causes of developmental delay and mental retardationand are usually associated with dysmorphic features. Karyotype shouldbe determined when one of these disorders is suspected.

Cytogenetic testing should also beconsidered in children with developmental delay but without dysmorphicfeatures even though the yield is low.

Molecular genetic testing to determinespecific mutations is now definitive diagnostic test for a numberof disorders.

Neuroimaging

Neuroimagingshould be performed in children with global delay when diagnosisis uncertain.

MRI is method of choice because ofits ability to detect subtle abnormalities of brain tissue. Candemonstrate involvement of gray matter, white matter, or both grayand white matter, which helps narrow diagnostic possibilities.

Metabolic Studies

Althoughnumber of metabolic disorders tested by newborn screening vary among differentstates, most states screen at least for phenylketonuria and hypothyroidism.

Metabolic brain disorders should beconsidered in individuals with developmental delay who have seizures,impaired vision, spasticity, ataxia, hepatosplenomegaly, or impairedcognitive function. When specific disorders are suspected, definitivetesting should be performed.

Screening tests for metabolic diseasesinclude serum electrolytes, glucose, creatinine, ammonia, lactate,pyruvate, and amino acids; blood urea nitrogen; liver function tests;and urine for mucopolysaccharide, and organic acid analysis.

Other investigations depend on resultsof these tests and suspected diagnosis.

Other Testing

Audiologictesting should be performed in children with specific language orglobal delays.

Ophthalmologic evaluation should beperformed, especially with any concerns about vision.

For suspected or definite seizures,electroencephalography should be performed.

Children with suspected neuromusculardisease should be referred to child neurologist for further evaluation,which may include electromyography, muscle U/S, nerve conductionstudies, and muscle biopsy.

See Chap.33, Hypotonia and Weakness.

References

1. Aicardi J. Diseases of the nervous systemin childhood, 2nd ed. London: Mac Keith Press, 1998.
2. Amir RE, et al. Rett syndrome is caused by mutationsin X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet1999;23:185–188.
3. Ball WS Jr, ed. Pediatric neuroradiology. Philadelphia:Lippincott-Raven, 1997.
4. Barkovich AJ. Pediatric neuroimaging, 3rd ed. Philadelphia:Lippincott Williams & Wilkins, 2000.
5. Batshaw ML. Mental retardation. Pediatr Clin NorthAm 1993;40:507–520.
6. Behrman RE, et al., eds. Nelson textbook of pediatrics,16th ed. Philadelphia: WB Saunders, 2000.
7. Clarke JTR. A clinical guide to inherited metabolicdiseases. Cambridge, U.K.: Cambridge University Press, 1996.
8. Curry CJ, et al. Evaluation of mental retardation:recommendations of a consensus conference. Am J Med Genet 1997;72:468–477.
9. Fenichel GM. Clinical pediatric neurology: a signsand symptoms approach, 4th ed. Philadelphia: WB Saunders, 2001.
10. First LR, Palfrey JS. The infant or young child withdevelopmental delay. N Engl J Med 1994;330:478–483.
11. Hofkosh D, Nalven LM. Developmental delay. In: GartnerJC Jr, Zitelli BJ, eds. Common & chronic symptoms in pediatrics.St. Louis: Mosby-Year Book, 1997:111–132.
12. Jones KL. Smith's recognizable patterns ofhuman malformation, 5th ed. Philadelphia: WB Saunders, 1997.
13. Lyon G, et al. Neurology of hereditary metabolic diseasesof children, 2nd ed. New York: McGraw-Hill, 1996.
14. McMillan JA, et al. Oski's pediatrics: principlesand practice, 3rd ed. Philadelphia: Lippincott Williams & Wilkins,1999.
15. Menkes JH, Sarnat HB, eds. Child neurology, 6th ed.Philadelphia: Lippincott Williams & Wilkins, 2000.
16. Online Mendelian Inheritance in Man (OMIM). McKusick-NathansInstitute for Genetic Medicine, Johns Hopkins University (Baltimore,MD) and National Center for Biotechnology Information, NationalLibrary of Medicine (Bethesda, MD), 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim.
17. Palfrey JS. Determining the etiology of developmentaldelay in very young children: what if we had a common internationallyaccepted protocol? J Pediatr 2000;136:569–570.
18. Roach ES, et al. Tuberous sclerosis complex consensusconference: revised clinical diagnostic criteria. J Child Neurol1998;13:624–628.
19. Rudolph AM, ed. Rudolph's pediatrics, 20thed. Stamford, CT: Appleton & Lange, 1996.
20. Scriver CR, et al., eds. The metabolic and molecularbases of inherited disease, 8th ed. New York: McGraw-Hill, 2001.
21. Shevell MI, et al. Etiologic yield of subspecialists' evaluationof young children with global developmental delay. J Pediatr 2000;136:593–598.
22. Suchy FJ, et al., eds. Liver disease in children, 2nded. Philadelphia: Lippincott Williams & Wilkins, 2001.
23. Swaiman KF, Ashwal S, eds. Pediatric neurology: principles & practice,3rd ed. St. Louis: CV Mosby, 1999.
24. Volpe JJ. Neurology of the newborn, 4th ed. Philadelphia:WB Saunders, 2001.

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Book Source Details

• Book Title: The Diagnostic Approach to Symptoms and Signs in Pediatrics
• Author(s): Paul S. Bellet
• Year of Publication: 2006
• Copyright Details: The Diagnostic Approach to Symptoms and Signs in Pediatrics, Copyright © 2006 Lippincott Williams & Wilkins.

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