Batten disease

Raphael Schiffmann MD (Dr. Schiffmann, Director of the Institute of Metabolic Disease at Baylor Research Institute, received research grants from Amicus Therapeutics, Protalix Biotherapeutics, and Shire.)
Originally released February 17, 1994; last updated December 18, 2016; expires December 28, 2019

This article includes discussion of Batten disease, Batten-Spielmeyer-Vogt disease, Jansky-Bielschowsky disease, Santavuori-Haltia disease, Kuf disease, infantile neuronal ceroid lipofuscinosis, late infantile neuronal ceroid lipofuscinosis, LINCL, variant of LINCL, juvenile neuronal ceroid lipofuscinosis, adult neuronal ceroid lipofuscinosis, congenital neuronal ceroid lipofuscinosis, and spinocerebellar neuronal ceroid lipofuscinosis. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Batten disease, or neuronal ceroid lipofuscinoses, constitutes one of the most common groups of inherited childhood-onset neurodegenerative disorders. They currently comprise 14 genetically distinct disorders, mostly characterized by progressive cognitive, motor, and visual impairment with onset in childhood, adolescence, and even adulthood. Abnormal autofluorescent, electron-dense granules accumulate in the cytoplasm of nerve cells and are associated with selective destruction and loss of neurons in the brain and retina. There are currently 14 different genes and over 360 mutations that underlie these devastating brain disorders. Gene therapy is the most promising form of therapy that is being developed.

Key points

 

• Neuronal ceroid lipofuscinoses, or Batten disease, are common neurodegenerative diseases of childhood.

 

• Typical clinical findings include retinopathy leading to blindness, sleep problems, motor abnormalities, myoclonic seizures, dementia, and premature death.

 

• Definitive diagnosis relies on enzymatic assays or DNA testing.

 

• A combination of cysteamine bitartrate and N-acetylcysteine may have some therapeutic benefits.

 

• Kufs disease or adult neuronal ceroid lipofuscinosis can be caused by 3 different genes and is often misdiagnosed pathologically.

Historical note and terminology

A detailed history of the classification and the pathological and clinical characteristics has been reviewed (Haltia and Goebel 2013). Neuronal ceroid lipofuscinosis consists of a group of genetically determined neurodegenerative disorders that affect children and adults of both sexes. The original description of the disorder is credited to Stengel, a Danish physician, who identified 4 children in a family from a rural village in Norway who had onset of visual failure in their sixth year, followed by progressive intellectual decline and loss of speech. Seizures began at 10 years, and they died in their twenties after remaining in a vegetative state for several years (Stengel 1826).

The visual loss and dementia noted in this disease led to its classification as a form of amaurotic familial idiocy, but an appreciation of the pathological differences, biochemical abnormalities, and genetic defects have established neuronal ceroid lipofuscinosis as a nosologic entity. The eponym Batten disease, now often associated with the juvenile form of the disease, is named for Frederick Batten, who, in 1903, described the cerebral and macular changes in 2 brothers (Batten 1903). Subsequently, Purkinje cells, gliosis, and the loss of cortical neurons in association with the pathognomonic accumulation of the autofluorescent lipopigments in the remaining neurons were documented and helped to distinguish Batten disease from other mental retardation syndromes (Vogt 1905; Bielschowsky 1913; Batten and Mayou 1915). Although the clinical features of the juvenile onset form were delineated in great detail (Spielmeyer 1908; Sjogren 1931), the adult variant was not recognized until 1925 (Kuf 1925). The high prevalence of an infantile onset form of Batten disease in Finland was later identified (Santavuori et al 1973), thereby uncovering the clinical spectrum of neuronal ceroid lipofuscinosis. Other subtypes, such as a variant of late infantile neuronal ceroid lipofuscinosis and a congenital form have been described (Lake and Cavanagh 1978; Dyken 1988). Advances in molecular genetics have led to the discovery of the gene defects for several of the variants (Mole 1996). The genetics of this group of disorders demonstrates that they are heterogeneous disorders with common pathologic and clinical features (See Table 1). The various subtypes of this disorder are collectively termed neuronal ceroid lipofuscinosis based on the nature of the symptoms and the characteristics of the stored material.

Table 1. Genetic Information of Neuronal Ceroid Lipofuscinosis Variants

Variant

Eponyms

Gene Name

Gene Product

Type of Protein

Infantile

Santavuori-Haltia Hagberg

CLN1

Palmitoyl protein thioesterase (PPT1)

Enzyme

Late infantile

Jansky-Bielschowsky

CLN2

Tripeptidyl peptidase 1 (TPP1)

Enzyme

Juvenile

Batten Vogt-Spielmeyer

CLN3

“Battenin”

Transmembrane

Adult

Kuf type A

CLN4A

?

Soluble cysteine string protein alpha

Adult

Kuf type B (A)

CTCF

Cathespin

Enzyme

Late infantile (Finnish)

?

CLN5

“Battenin”

Soluble

Late infantile (Portuguese or Costa Rican)

?

CLN6

?

Transmembrane

Late infantile (Turkish)

?

CLN7

?

Transmembrane, lysosomal

Late infantile (northern epilepsy mental retardation) (TLC protein class)

?

CLN8

?

Transmembrane, ER

Juvenile

?

CNL9

?

?

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