Psychomotor Retardation and Regression

Clinical features

The major diagnostic criteria are impaired sociability, impaired verbal and nonverbal communication skills, and restricted activities and interests. Failure of language development is the feature most likely to bring autistic infants to medical attention and correlates best with the outcome; children who fail to develop language before age 5 years have the worst outcome. The IQ is less than 70 in most children with autism. However, IQ may be significantly underestimated due to their impaired interactive skills, which make testing difficult and less reliable. Some autistic children show no affection to their parents or other care providers, while others are affectionate on their own terms. Autistic children do not show normal play activity; some have a morbid preoccupation with spinning objects, stereotyped behaviors such as rocking and spinning, and relative insensitivity to pain. An increased incidence of epilepsy in autistic children is probable.

Diagnosis

Infantile autism is a clinical diagnosis and not confirmable by laboratory tests. Chromosomal microarray analysis (CMA) provides a possible genetic susceptibility in many cases, but it is not a diagnostic test. The pattern of inheritance is very complex and likely multifactorial, which limits the use of CMA as a diagnostic tool. However, identifying a genetic susceptibility may be of benefit to the family by allowing access to better resources for autism, exposure to any specifics in the literature associated with the genetic diagnosis, limiting further diagnostic testing, and perhaps providing information regarding the risk for the rest of family or future pregnancies. Infants with profound hearing impairment may display autistic behavior, and tests of hearing are diagnostic. Electroencephalography (EEG) is indicated when seizures are suspected and to evaluate the less likely possibility of Landau-Kleffner syndrome. The study should be obtained with sedation in most cases, since sleep recording is needed and autistic children often become distressed by the procedure and do not cooperate with electrode placement.

Management

Autism is not curable, but several drugs may be useful to control specific behavioral disturbances. Behavior modification techniques improve some aspects of the severely aberrant behavior. However, despite the best program of treatment, these children function in a moderate to severe cognitive impaired range, despite their level of intelligence. In our experience, many children benefit from the use of selective serotonin reuptake inhibitors. Citalopram 10–20 mg/day, escitalopram 5–10 mg/day, and sertraline 50–100 mg/day are commonly used. Children with ASD often suffer from anxiety and obsessive-compulsive behaviors that may interfere with their development and social skills. Obsessive-compulsive traits are often difficult to discern in patients with autism. Autistic children are typically unable to express themselves, and their obsessive thinking only becomes visible when associated with compulsions. Therefore a trial with the above medications should be offered in most cases. Many children also benefit from a management of hyperactive behaviors when present. Clonidine 0.05–0.1 mg bid or guanfacine 0.5–1 mg bid are good options. Atomoxetine (Strattera) and stimulants are also an option. Risperidone (Risperdal) and aripiprazole (Abilify) are helpful treating the irritability, aggressiveness, or self-injurious behaviors exhibited by some children with ASD. The starting dose of risperidone is 0.25–0.5 mg and may be increased by those amounts every 2 weeks up to 3 mg daily if needed and tolerated. Children and adolescents with comorbid bipolar mania or schizophrenia may need up to 6 mg/day. The starting dose of Abilify is 2–5 mg and may be increased weekly up to 15–30 mg daily.

Clinical features

Males with a complete phenotype have a characteristic appearance (large head, long face, prominent forehead and chin, protruding ears), connective tissue findings (joint laxity), and large testes after puberty. Behavioral abnormalities are common. The phenotypic features of males with full mutations vary in relation to puberty. Prepubertal males grow normally, but have an occipitofrontal head circumference larger than the 50th percentile. Achievement of motor and speech milestones is late and temperament is abnormal, sometimes suggesting autism. Other physical features that become more obvious after puberty include: a long face, prominent forehead, large ears, prominent jaw, and large genitalia.

The phenotype of females depends on both the nature of the FMR1 mutation and random X-chromosome inactivation. About 50% of females who inherit a full fragile X mutation are cognitively impaired; however, they are usually less severely affected than males with a full mutation. Approximately 20% of males with a fragile X chromosome are normal, while 30% of carrier females are mildly affected. An asymptomatic male can pass the abnormal chromosome to his daughters, who are usually asymptomatic as well. The daughters’ children, both male and female, may be symptomatic.

Diagnosis

The FMR1 gene at Xq27.3 normally contains 5–40 consecutive trinucleotide repeats (CGGs). When 55–200 repeats are present, the gene is prone to further expansion during meiosis. A full expansion of more than 200 repeats is associated with the phenotype of fragile X syndrome.

Management

Treatment consists of pharmacological management for behavior problems and educational intervention.

Clinical features

Infection of the fetus is transplacental. Two-thirds of infected newborns are asymptomatic and are identified only on screening tests. The more common features in symptomatic newborns and infants are hepatosplenomegaly, periostitis, osteochondritis, pneumonia (pneumonia alba), persistent rhinorrhea (snuffles), and a maculopapular rash that can involve the palms and soles. If left untreated, the classic stigmata of Hutchinson teeth, saddle nose, interstitial keratitis, saber shins, cognitive impairment, hearing loss, and hydrocephalus develop.

The onset of neurological disturbances usually begins after 2 years of age and includes eighth nerve deafness and cognitive impairment. The combination of nerve deafness, interstitial keratitis, and peg-shaped upper incisors is the Hutchinson triad.

Diagnosis

Syphilis screening is typically performed as part of routine prenatal care. All newborns to a mother with reactive nontreponemal (RPR, VDRL) and treponemal test (TP-PA, FTA-ABS, EIA, CIA) results, should be evaluated with a quantitative nontreponemal serological test performed on the neonate's serum. Cebrospinal fluid (CSF) should be obtained for VDRL, cell count, and protein to address the question of neurosyphilis. The CSF is abnormal in about 10% of asymptomatically infected infants. Suspect concomitant HIV infection in every child with congenital syphilis.

Management

The CDC recommends one of two regimens for treatment of an infant born to a woman with any stage of syphilis, who has not received appropriate treatment during gestation, or for whom the possibility of congenital syphilis cannot be ruled out: (1) Aqueous crystalline penicillin G 100,000–150,000 units/kg/day administered intravenously every 12 hours at a dose of 50,000 units/kg/dose during the first 7 days of life and every 8 hours thereafter for a total of 10 days, or (2) Procaine penicillin G 50,000 units/kg/dose intramuscular (IM) in a single daily dose for 10 days up to the adult maximum dose of 2.4 million units/dose. Consultation with an infectious disease specialist is advised.

Clinical features

Approximately 10%–15% of infected newborns are symptomatic. Clinical manifestations include intrauterine growth retardation, jaundice, petechiae/purpura, hepatosplenomegaly, microcephaly, hydrocephaly, intracerebral calcifications, glaucoma, seizures, and chorioretinitis. Except for the brain, most organ involvement is self-limited.

Migrational defects (lissencephaly, polymicrogyria, and cerebellar agenesis) are the main consequence of fetal infection during the first trimester. Some infants have microcephaly secondary to intrauterine infection without evidence of systemic infection at birth.

Diagnosis

The virus must be isolated within the first 3 weeks of life to confirm congenital infection. Afterwards virus shedding no longer differentiates congenital from postnatal infection. Although CMV can be isolated from many sites, urine and saliva are preferred samples for congenital CMV infection because of their viral content. For these samples, a technique using monoclonal antibodies to detect CMV is diagnostic. Detection of CMV DNA by polymerase chain reaction (PCR) or in situ hybridization of tissues and fluids is also available. Infected newborns should be isolated from women of childbearing age.

In infants with developmental delay and microcephaly, establishing the diagnosis of cytomegalic inclusion disease is by serological demonstration of prior infection and a consistent pattern of intracranial calcification.

Management

Much of the brain damage from congenital CMV occurs in utero; however, the use of ganciclovir orally at a dose of 16 mg/kg divided twice daily, modestly improved hearing and developmental outcomes when given to affected newborns for 6 months postnatally.

Clinical features

The lymphocytic choriomeningitis virus (LCMV) causes minor respiratory symptoms when inhaled, and frequently is entirely asymptomatic. Common house mice are the vector, and an estimated 2%–5% of adults have antibodies to the virus. However, the Centers for Disease Control and Prevention (CDC) recognizes fetal infection as a common and likely underreported cause of multiple CNS malformations, particularly hydrocephaly. Other sequelae include migrational abnormalities, microcephaly, periventricular calcifications, pachygyria, and periventricular or porencephalic cysts. The eye findings may include chorioretinal lacunae, panretinal pigment epithelium atrophy, optic nerve hypoplasia, and reduced caliber of retinal vessels.

LCMV is a common cause of hydrocephalus. Up to one-third of newborns with hydrocephalus have positive serology to LCMV, and conversely almost 90% of children with serologically confirmed perinatal infection with LCMV have hydrocephalus. Almost 40% have hydrocephalus at birth; the remainder develop it over the first 3 months of age. Blindness and ID are potential long-term complications. Outcome severity depends on the timing of infection; early infection produces the worse outcomes.

Diagnosis

Imaging of the brain reveals major malformations. Viral culture of blood, CSF, and urine are diagnostic. Immunofluorescent antibody tests or enzyme-linked immunosorbent assays are currently available for serum and CSF. PCR for detection of LCMV ribonucleic acid (RNA) in urine, CSF, and serum is possible. Infections in older immunocompetent children are usually asymptomatic or a minor febrile illness, but meningoencephalitis may occur in the immunocompromised.

Management

Much of the brain damage from congenital LCMV occurs in utero and is not influenced by postnatal treatment.

Diagnosis

HIV DNA PCR is the preferred method for the diagnosis of HIV infection in infants and children younger than 18 months of age.

Management

The antiretroviral zidovudine reduces the infection rate by 70% when given to infected women during pregnancy and delivery, and given to the newborn for 6 weeks after birth. The current transmission rates to exposed newborns is less than 1% if treatment is provided and the mother avoids breastfeeding. The current standard of care is to initiate any infected and breastfeeding woman on life-long antiretroviral therapy regardless of her CD4 + counts. Such interventions have decreased the number of infected infants worldwide from 520,000 in 2000, to 220,000 in 2014. In contrast, the mortality rate of untreated infants in sub-Saharan Africa is 53% by age 2 and 75% by age 3 years.

Clinical features

Rubella embryopathy is a multisystem disease characterized by intrauterine growth retardation, cataracts, chorioretinitis, congenital heart disease, sensorineural deafness, hepatosplenomegaly, jaundice, anemia, thrombocytopenia, and rash. Eighty percent of children with a congenital rubella syndrome have nervous system involvement. The neurological features are bulging fontanelle, lethargy, hypotonia, and seizures. Seizure onset is from birth to 3 months of age.

Diagnosis

In order to provide accurate counseling, make every effort to confirm rubella infection in the exposed pregnant woman. Virus isolation is complicated and the diagnosis is established best by documenting rubella-specific IgM antibody in addition to a 4-fold or greater rise in rubella-specific IgG.

Management

Prevention is by immunization and avoiding possible exposure during pregnancy. No treatment is available for active infection in the newborn.

Clinical features

One-quarter of infected newborns have multisystem involvement (fever, rash, hepatosplenomegaly, jaundice, and thrombocytopenia) at birth. Neurological dysfunction is manifest as seizures, altered states of consciousness, and increased intracranial pressure. The triad of hydrocephalus, chorioretinitis, and intracranial calcification is the hallmark of congenital toxoplasmosis in older children. About 8% of infected newborns who are asymptomatic at birth later show neurological sequelae, especially psychomotor retardation.

Diagnosis

Detection of the organism is diagnostic, as are commercially available serological techniques. Presume any patient with positive IgG and IgM titers to be recently infected. The sensitivity of CSF PCR is only about 50%.

The presence of positive or rising IgM and IgG titers confirms acute T. gondii infection in a pregnant woman. Detection of T. gondii DNA in amniotic fluid by PCR is less invasive and more sensitive than isolating parasites from fetal blood or amniotic fluid. Serial fetal ultrasonographic examinations monitoring for ventricular enlargement and other signs of fetal infection is recommended.

In older children, the diagnosis requires not only serological evidence of prior infection but also compatible clinical features.

Management

A combined prenatal and postnatal treatment program for congenital toxoplasmosis can reduce neurological morbidity. When seroconversion indicates acute maternal infection, fetal blood and amniotic fluid are cultured and fetal blood tested for Toxoplasma -specific IgM. Treat with spiramycin monotherapy unless proven fetal infection exists, in which case add pyrimethamine, and sulfadoxine. In newborns with clinical evidence of toxoplasmosis, treat with pyrimethamine (Daraprim) and sulfadiazine for 1 year. Because pyrimethamine is a folic acid antagonist, administer folinic acid (leucovorin) during therapy and for 1 week after termination of treatment. Routine monitoring of the peripheral platelet count is required. Newborns with a high protein concentration in the CSF or chorioretinitis also require prednisone 1–2 mg/kg/day. The optimal duration of therapy for congenital toxoplasmosis is unknown, but 1 year is the rule. Because of the high likelihood of fetal damage, termination of pregnancy may be considered if fetal infection is confirmed at less than 16 weeks gestation, or if the fetus shows evidence of hydrocephalus.

Clinical features

Evidence of infection is apparent during the first year in 30% of children born to AIDS-infected mothers. As a rule the outcome is worse when the onset of symptoms is early, and the rate of progression in the child relates directly to the severity of disease in the mother.

Twenty percent of children with HIV present with severe symptoms or die in infancy. The cause of their poor prognosis is unknown. The spectrum of neurological and non-neurological manifestations in HIV-infected children is somewhat different from adults. Hepatosplenomegaly and bone marrow failure, lymphocytic interstitial pneumonia, chronic diarrhea, failure to thrive, acquired microcephaly, cerebral vasculopathy, and basal ganglia calcification occur more frequently in children. Opportunistic infections that represent recrudescence of previously acquired infections in adults, e.g., cerebral toxoplasmosis or progressive multifocal leukoencephalopathy, are rare in infants.

AIDS encephalopathy may be subacute or indolent and is not necessarily associated with failure to thrive or opportunistic infections. The onset of encephalopathy may occur from 2 months to 5 years after exposure to the virus. Ninety percent of affected infants show symptoms by 18 months of age. Progressive loss of developmental milestones, microcephaly, dementia, and spasticity characterize the encephalopathy. Other features seen in less than 50% of children are ataxia, pseudobulbar palsy, involuntary movement disorders, myoclonus, and seizures. Death usually occurs a few months after the onset of AIDS encephalopathy.

Diagnosis

HIV DNA PCR is the preferred method for the diagnosis of HIV infection in infants and children younger than 18 months of age. It is performed on peripheral blood mononuclear cells and is highly sensitive and specific by 2 weeks of age. Approximately 30% of infants with HIV infection will have a positive DNA PCR assay result by 48 hours, 93% by 2 weeks, and almost all infants by 1 month of age.

Management

The introduction of routine maternal treatment with highly active antiretroviral therapy (HAART) in 1996 greatly decreased the incidence of pediatric AIDS. Combined treatment with zidovudine (azidothymidine, AZT), didanosine, and nevirapine is well tolerated and may have sustained efficacy against HIV-1. Bone marrow suppression is the only important evidence of toxicity.

Clinical features

Affected children appear normal at birth and may develop normally during infancy. By the end of the first year, development fails to progress and hypotonia is noted. Regression of development follows and may be associated with dyskinesias, dystonia, myoclonic jerks, autism, and seizures refractory to standard anticonvulsant treatment.

Diagnosis

MRI reveals marked demyelination and magnetic resonance spectroscopy shows creatine depletion and guanidinoacetate phosphate accumulation. GAMT deficiency can be identified by elevated guanidinoacetate in newborn blood with virtually absent false-positive results. This is an ideal candidate for inclusion on neonatal screening tests, as it is treatable and the outcome depends on prompt treatment initiation.

Management

Treatment includes creatine monohydrate at doses between 300 and 800 mg/kg/day, L-ornithine aspartate or hydrochloride at doses between 100 and 800 mg/kg/day, and sodium benzoate at 100 mg/kg/day. These medications in combination with a low-protein, low-arginine diet, prevent or reverse symptomatology in GAMT deficiency.

Clinical features

Affected individuals appear normal at birth. Neurological features include mild to moderate cognitive impairment, developmental delay, psychiatric/behavioral symptoms, seizures, and extrapyramidal symptoms. Non-neurological features include ectopia lentis or severe myopia, marfanoid appearance, osteoporosis, pectus excavatum, genu valgum, scoliosis, and cerebral thromboembolism. Intelligence is generally higher in B ₆ -responsive than B ₆ -nonresponsive homocystinuria.

High plasma homocysteine concentrations adversely affect collagen metabolism and are responsible for intimal thickening of blood vessel walls, leading to arterial and venous thromboembolic disease. Cerebral thromboembolism is a life-threatening complication. Emboli may occur in infancy, but are seen more frequently in adult life. Young adult heterozygotes are also at risk. Occlusion of the coronary or carotid arteries can lead to sudden death or severe neurological handicap. Thromboembolism is the first clue to the diagnosis in 15% of cases.

Dislocation of the lens, an almost constant feature of homocystinuria, typically occurs between 2 and 10 years of age. Almost all patients have lens dislocation by age 40 years. Older children have osteoporosis, often first affecting the spine resulting in scoliosis. Many children are tall and thin, with blond, sparse, brittle hair and a Marfan syndrome habitus. This habitus does not develop until middle or late childhood and serves as a clue to the diagnosis in fewer than 40% of cases.

The diagnosis is suspect in any infant with isolated and unexplained developmental delay, since disease-specific features may not appear until later childhood. The presence of either thromboembolism or lens dislocation strongly suggests homocystinuria.

Diagnosis

The biochemical features of homocystinuria are increased concentrations of plasma homocystine, total homocysteine, and methionine; increased concentration of urine homocystine; and reduced cystathionine β-synthase enzyme activity. The main test for diagnosis of cystathionine beta-synthase (CBS) deficiency is the measurement of the total homocysteine (tHcy) in plasma. Molecular genetic diagnosis is available.

Prenatal diagnosis is available for fetuses at risk by measurement of cystathionine β-synthase enzyme activity assayed in cultured amniocytes, but not in chorionic villi, since this tissue has low enzyme activity at baseline.

Management

All patients with homocystinuria should receive 10 mg/kg/day of pyridoxine, up to a maximum of 500 mg/day for 6 weeks. Plasma tHcy is measured twice before treatment and twice during treatment; the test should not be done if the patient is catabolic. The protein intake should be normal, folate supplements should be given, and vitamin B ₁₂ deficiency should be corrected prior to testing. Patients who achieve plasma tHcy levels below 50 μmol/L on pyridoxine are clearly B ₆ responsive and do not need any other treatment. Folate and vitamin B ₁₂ optimize the conversion of homocysteine to methionine and help to decrease homocysteine levels. If the tHcy falls more than 20%, but remains above 50 μmol/L, additional treatment should be considered (i.e., diet and/or betaine). If tHcy falls by less than 20% on B ₆ , the patient is not responsive to B ₆ .

Treatment with betaine, starting at 100 mg/kg/day with increments of 50 mg/g/day weekly up to 200 mg/kg/day or a max of 3 g/day in two divided doses, provides an alternate remethylation pathway by donation of a methyl group to convert excess homocysteine to methionine and may help prevent thrombosis.

Clinical features

Deficiency is associated with several different phenotypes. Three recognized clinical phenotypes are classic , intermittent , and intermediate . An acute encephalopathy with ketoacidosis characterizes the classic and intermittent forms (see Chapters 1 and 10 ). The levels of dehydrogenase enzyme activity in the intermediate and intermittent forms are approximately the same (5%–40%), whereas activity in the classic form is 0%–2% of normal.

The onset of the intermediate form is late in infancy, often in association with a febrile illness or a large protein intake. In the absence of vigorous early therapeutic intervention, moderate cognitive impairment results. Ataxia and failure to thrive are common. Infants with intermediate MSUD are slow in achieving milestones and are hyperactive. As children, they generally function in the moderately cognitively impaired range of intelligence. Physical development is normal except for coarse, brittle hair. The urine may have the odor of maple syrup. As a general rule, acute mental changes, seizures, and focal neurological deficits do not occur.

Some infants with the intermediate form are thiamine responsive. In such children, cognitive impairment is moderate.

Diagnosis

Branched chain amino acid and branched chain ketoacid concentrations are elevated, although not as high as in the classic disease. A presumptive diagnosis requires the demonstration of branched chain amino acids in the urine by a ferric chloride test or the 2,4-dinitrophenylhydrazine test. Quantitative measurement of blood and urine BCAA and BCKA is diagnostic.

Treatment

Treatment of MSUD includes dietary leucine restriction, high-calorie BCAA-free formulas, and frequent monitoring. Correct metabolic decompensation by treating the precipitating stress and delivering sufficient calories, insulin, free amino acids, isoleucine, and valine, and in some centers, hemodialysis/hemofiltration, to establish net positive protein accretion.

A protein-restricted diet is the main treatment of infants with intermediate MSUD. In addition, a trial of thiamine 100 mg/day, tests if the biochemical error is thiamine responsive. If 100 mg is not effective, try daily dosages up to l g of thiamine before designating the condition as thiamine refractory. Brain edema, a common potential complication of metabolic decompensation, requires immediate therapy in an intensive care setting. Hemodialysis may help in this setting, in addition to BCAA restriction and caloric support.

Orthotopic liver transplantation is an effective therapy for classic MSUD. Frequent monitoring of plasma amino acid concentrations and fetal growth is necessary to avoid essential amino acid deficiencies during pregnancy.

Clinical features

Because affected children are normal at birth, early diagnosis requires compulsory mass screening. The screening test detects HPA, which is not synonymous with PKU ( Box 5.6 ). Blood phenylalanine and tyrosine concentrations must be precisely determined in every newborn detected by the screening test in order to differentiate classic PKU from other conditions. In newborns with classic PKU, HPA develops 48–72 hours after initiation of milk feeding. Blood phenylalanine concentrations are 20 mg/dL or greater, and serum tyrosine levels are less than 5 mg/dL. When blood phenylalanine concentrations reach 15 mg/dL, phenylalanine spills over into the urine and the addition of ferric chloride solution (5–10 drops of FeCl to l mL of urine) produces a green color.

During the first months, the skin may have a musty odor because of phenylacetic acid in the sweat. Developmental delay is sometimes obvious by the third month and always before the end of the first year. By the beginning of the second year, developmental regression is evident. Behavioral disturbances characterized by hyperactivity and aggressiveness are common; focal neurological deficits are unusual. Approximately 25% of affected infants have seizures. Some have infantile spasms and hypsarrhythmia; others have tonic-clonic seizures. Infants with phenylketonuria frequently have blond hair, pale skin, and blue eyes owing to diminished pigment production. Eczema is common. These skin changes are the only non-neurological features of phenylketonuria.

Diagnosis

Newborn screening detects all cases of PKU. The screening test detects the presence of HPA. Plasma amino acid analysis including phenylalanine concentration, phenylalanine to tyrosine ratio, and a complete amino acid profile confirms the diagnosis. Plasma phenylalanine concentrations above 1000 μmol/L in the untreated state are diagnostic. The use of molecular genetic testing is primarily for genetic counseling and prenatal testing. Blood phenylalanine levels less than 25 mg/dL and a normal concentration of tyrosine characterize benign variants of phenylketonuria. Disturbances in tetrahydrobiopterin underlie the malignant forms of phenylketonuria. Seizures are the initial symptom and cognitive impairment and motor deficits come later. Progressive calcification of the basal ganglia occurs in untreated children.

Transitory tyrosinemia occurs in 2% of full-term newborns and in 2% of premature newborns. The cause is a transitory deficiency of the enzyme p -hydroxyphenylpyruvic acid. It is a benign condition and can be distinguished from PKU because the blood concentrations of both tyrosine and phenylalanine are elevated.

Management

In classic PKU, initiate a low-protein diet and use of a phenylalanine-free medical formula as soon as possible after birth to achieve plasma phenylalanine concentrations of 120–360 μmol/L (2–6 mg/dL), or 40–240 μmol/L (1–4 mg/dL). Recent studies suggest that the plasma phenylalanine goal should be ≤ 240 μmol/L to expect normal neurocognitive outcomes. Dietary supplementation with 6 R -BH4 stereoisomer in doses up to 20 mg/kg daily depends on individual needs. Treatment of infants with non-PKU HPA with plasma phenylalanine concentrations consistently less than 600 μmol/L is uncertain.

BH4 is a cofactor for phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase. Defective recycling or synthesis causes deficiency. In infants with cofactor deficiency, a phenylalanine-restricted diet reduces the blood phenylalanine concentration, but does not prevent neurological deterioration. For these children, BH4 administration is the therapy of choice.

Clinical features

Symptom onset in infants with Gaucher disease type II is usually before 6 months of age and frequently before 3 months of age. The initial features are motor regression and cranial nerve dysfunction. Children are first hypotonic and then spastic. Head retraction, an early and characteristic sign, probably is due to meningeal irritation. Difficulties in sucking and swallowing, trismus, and oculomotor palsies are typical. Mental deterioration is rapid, but seizures are uncommon. Splenomegaly is more prominent than hepatomegaly, and jaundice is not expected. Hypersplenism results in anemia, thrombocytopenia, and leukopenia. Death usually occurs during the first year and always by the second.

Diagnosis

Assay of acid β-glucosylceramidase enzyme activity in peripheral blood leukocytes or other nucleated cells is reliable for diagnosis. Glucosylceramidase enzyme activity in peripheral blood leukocytes is 0%–15% of normal. Carrier detection and prenatal diagnosis are available. Molecular genetic testing is available, but biochemical testing may still be required to confirm the diagnosis.

Management

Symptomatic treatment for Gaucher disease includes partial or total splenectomy for massive splenomegaly and thrombocytopenia, transfusion of blood for severe anemia and bleeding, analgesics for bone pain, joint replacement surgery for relief from chronic pain and restoration of function, and supplemental treatment such as oral bisphosphonates for severe osteopenia.

Patients with type III disease may benefit from bone marrow transplantation to correct the metabolic defect. Enzyme replacement therapy, using imiglucerase, is effective in reversing the hematological and liver/spleen involvement. Substrate reduction therapy (SRT) is also used.

Clinical features

The median age of onset is 4 months, with a range of 1–7 months. Initial symptoms are irritability and hyperreactivity to stimuli. Progressive hypertonicity in the skeletal muscles follows. Unexplained low-grade fever is common. Psychomotor development arrests and then regresses. Within 2–4 months, the infant is in a permanent position of opisthotonos and all previously achieved milestones are lost. Tendon reflexes become hypoactive and disappear. Startle myoclonus and seizures develop. Blindness occurs, and before 1 year 90% of these infants are either dead or in a chronic vegetative state.

Several variant forms of globoid leukodystrophy with different clinical features exist: infantile spasm syndrome (see Chapter 1 ), focal neurological deficits (see Chapters 10 and 11 ), and polyneuropathy (see Chapter 7 ). The juvenile form will be discussed later in this chapter.

Diagnosis

MRI shows diffuse demyelination of the cerebral hemispheres (see Fig. 5.1 ). Motor nerve conduction velocity of peripheral nerves is usually prolonged, and the protein content of CSF elevated. Deficient activity of galactocerebrosidase in leukocytes or cultured fibroblasts establishes the diagnosis. Molecular genetic testing is not the diagnostic test of choice, although it is available. Several states are considering adding Krabbe disease to the standardized newborn screen.

Management

Hematopoietic stem cell transplantation slows the course of disease in children with infantile-onset Krabbe disease diagnosed before symptom onset. Neurological manifestations may reverse, but peripheral nervous system disease may continue to progress.