Neuronal Ceroid Lipofuscinoses

Hereditary progressive neurodegenerative disorders with mental retardation, visual loss (retinitis pigmentosa), and seizures. Neuronal ceroid lipofuscinoses are probably the most common class of neurodegenerative disease in children.

Four types of neuronal ceroid lipofuscinoses are described in the literature. They are characterized by intralysosomal accumulations of autofluorescent lipopigment in various tissues.

Type I: Infantile Neuronal Ceroid Lipofuscinosis (Finnish Infantile Neuronal Ceroid Lipofuscinosis Type; Infantile Neuronal Ceroid Lipofuscinoses; Santavuori Disease; Santavuori-Haltia Disease).

Type II: Late Infantile Neuronal Ceroid Lipofuscinosis (Jansky-Bielschowsky Disease; Late Infantile Type of Amaurotic Idiocy; Late Infantile Batten Disease): A few variants of this form of neuronal ceroid lipofuscinosis are determined by the mutation on the gene map locus 15q21-q23. Three variants have been described: (A) neuronal ceroid lipofuscinosis variant 6, which corresponds to mutations in the CLN6 gene; (B) Turkish neuronal ceroid lipofuscinosis variant 8 (also called northern progressive epilepsy with mental retardation syndrome), which is caused by mutation in the CLN8 gene; and (C) Finnish neuronal ceroid lipofuscinosis variant 5, which is caused by mutation in the CLN5 gene.

Type III: Juvenile Neuronal Ceroid Lipofuscinosis (Infantile Batten Disease; Vogt-Spielmeyer Disease; Amaurotic Familial Idiocy of the Juvenile Type): One genetic variant of the Batten juvenile form of neuronal ceroid lipofuscinosis has been described and consists of the presence of granular osmiophilic deposits (GROD) and the absence of fingerprint curvilinear bodies. Clinically, these patients demonstrate learning disabilities beginning at ages 6 and 10 years but visual failure is delayed until age 14 years.

Type IV: Adult Neuronal Ceroid Lipofuscinosis (Kufs Disease; Autosomal Recessive Kufs Disease): Autosomal dominant form has been described for the Kufs disease and is characterized by progressive neurodegenerative diseases but absence of ocular involvement.

1:20,000 in the general population of Finland for early infantile and juvenile forms to 1:150,000 in the general population.

All neuronal ceroid lipofuscinoses are autosomal recessive and are genetically independent.

Precise pathogenesis and etiology of this group of diseases are elusive. The common defect underlying all neuronal ceroid lipofuscinoses affects lysosomal function characterized by intralysosomal accumulation of an autofluorescent lipopigment in the perikaryon of different neuronal cell types in granula, curvilinear, or fingerprint patterns. Clinically, this results in a profound degenerative impact on the central nervous system. In addition to the diseases outlined, numerous atypical variants indicated in the classification of neuronal ceroid lipofuscinoses account for approximately 10 to 20% of patients. Several eponymous names are associated with these disorders, which are sometimes collectively known as Batten disease.

Young patients with gradual onset of blindness and neurologic signs, retinitis pigmentosa, and epilepsy should be examined for neuronal ceroid lipofuscinosis. Urinary dolichol level is raised, and biopsy of the skin or conjunctiva demonstrates characteristic lipofuscin storage.

The early juvenile form results in death within the first decade of life. The later-onset forms are associated with dementia and a slower decline.

Thorough history and physical examination should reveal the extent of the disorder. Of particular note to the anesthesiologist is the presence of epilepsy. A thorough history of medication use is necessary because these patients may be on long-term anticonvulsant therapy or psychotropic medication.

No specific indications or contraindications for specific anesthetic techniques. However, in the face of neurointellectual impairment, awake regional techniques may be inappropriate. The presence of microcephaly with history of developmental delay or regression of neurologic development should indicate need to reduce anesthetic doses. Seizure medications must be supplemented intravenously during the surgical procedure.

Carefully select anticonvulsant agents. Proconvulsant agents probably are contraindicated for patients with this condition, whether or not they have a history of convulsions. The use of sevoflurane should be done cautiously.

Alpers Disease: Usually characterized by a clinical triad of psychomotor retardation and mental deterioration; intractable epilepsy; and liver failure in infants and young children. The illness usually begins in early life with severe convulsions unresponsive to anticonvulsant drug therapy (intractable epilepsy). Progressive neurologic disorder characterized by spasticity, myoclonus, and dementia. Status epilepticus is often the terminating development. Definitive diagnosis is shown by postmortem examination of the brain and liver.

Rett Syndrome: Rare progressive neurologic disorder that occurs only in females. Affected children appear to develop normally until approximately 6 to 18 months of age, at which time a dramatic change in development is noticeable, even signs of regression become obvious. Other clinical features include a stop of calvarium and brain development leading to microcephaly by age 1 year. As the disorder progresses, stereotypical hand movements (e.g., rubbing and “hand washing”) are characteristic of this medical condition. Hyperventilation, seizure episodes, and progressive loss of additional motor abilities can be present.

Gangliosidosis (GM2) Type II: Heritable lysosomal storage disorder with ganglioside accumulation leading to severe neurologic impairment and premature death.

Leigh Syndrome: Severe progressive necrotizing encephalopathy caused by a mitochondrial disorder impeding oxidative phosphorylation.

Variant Janski Bielschowski Syndrome (Lake and Cavanagh Disease): Onset is between 4 and 5 years of age, with mild motor rand mental problems; myoclonias, seizures, and visual loss occur before age 10 years. Death after 20 years.

Haltia-Santavuori Syndrome

At a Glance

Hypotonia, seizures, and visual loss beginning between 3 and 18 months of age.

Genetic Inheritance

Gene maps on locus 1p32, coding for the lysosomal glycoprotein palmitoyl-thioesterase.

Clinical Aspects

Onset between 3 and 18 months of age, with hypotonia, microcephaly, myoclonic seizures, intellectual and psychomotor retardation, and progressive loss of vision caused by macular degeneration before age 2 years. Stereotyped movements of the hands. Cerebellar ataxia is prominent. Electroencephalogram (EEG) tracing rapidly becomes isoelectric (“vanishing EEG”). Cerebral and cerebellar atrophy and thalamic hypodensity on MRI. Death between 5 and 10 years of age.

Janski Bielschowski Syndrome

At a Glance

Dementia, seizures, and visual loss beginning between the ages of 2 and 4 years.

Incidence and Genetic Inheritance

Most common in Newfoundland, Canada. Gene map locus is 11p15.5, coding for a lysosomal peptidase.

Clinical Aspects

Onset between the ages of 2 and 4 years, presenting with myoclonic seizures, rapid mental deterioration, quadriparesis, dementia, and ataxia. Cerebellar dysfunction is more severe than in Vogt-Spielmeyer syndrome. Retinal degeneration in these patients is most pronounced in the area of the macula but also affects the rest of the retina, resulting in blindness. Optic nerve atrophy is remarkable.

References

Vogt-Spielmeyer Syndrome

At a Glance

Rapid, progressive deterioration of vision and a slower but progressive deterioration of the intellect. Lack of motor control, psychotic behavior, and seizures develop later, with onset at about 10 years of age.

Genetic Inheritance

Gene map locus is 16p12.1-11.2.

Clinical Aspects

Compared to the other forms, onset is later, at around 10 years of age. It is characterized by rapid and progressive deterioration of vision (because of tapetoretinal degeneration with retinal atrophy) and slower and progressive intellectual deterioration (progressive dementia, cerebellar disturbances, seizures, psychomotor regression, psychosis, and brain atrophy). Prenatal diagnosis on chorionic villus samples is possible. Accumulation of an autofluorescent lipopigment has been found not only in the perikaryon of different neuronal cell types but also in extraneuronal cells. Vacuolization of lymphocytes is another finding in these patients, affecting up to two thirds of lymphocytes. Myoclonic fitting is less prominent in the later-onset group, but dystonic posturing and antisocial activity are more pronounced features.

References

Kufs Disease

At a Glance

Very rare disorder marked initially by progressive muscle weakness with ataxia, generalized seizures, chorea athetosis, and rarely blindness. It is linked to excess accumulations of lipofuscins throughout the central nervous system.

Incidence

Estimated to be 2-4:100,000 live births in the United States. The prevalence of this medical condition appears more frequently in northern Europe (Finland, Sweden) than in other international regions.

Genetic Inheritance

Inherited disorder; either autosomal recessive (Kufs disease) or autosomal dominant form often known as a variant of Kufs disease and called Parry disease. Recessive form is more serious than the dominant form.

Pathophysiology

This medical entity is often considered a variant of the juvenile neuronal ceroid lipofuscinosis. However, it is known to have an onset age between 20 and 32 years. Symptoms are the result of excessive accumulation of lipofuscins in the brains.

Clinical Aspects

Confusion, stupor, or psychotic behavior may be the initial symptoms manifested by the individual. Mental retardation and generalized convulsions follow. Patients affected with this medical entity also present ichthyosis vulgaris that results from excess production and/or retention of keratin.

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