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APBD is a glycogen storage disorder (GSD), which manifests as a debilitating and fatal progressive axonopathic leukodystrophy. It further characterized by peripheral neuropathy, dysautonomia, urinary incontinence, and occasionally dementia, all being important diagnostic criteria for this commonly misdiagnosed and widely heterogeneous disease.

APBD is caused by glycogen branching enzyme (GBE) deficiency leading to poorly branched and therefore insoluble glycogen, called polyglucosan, which precipitate, aggregate, and accumulate into polyglucosan bodies.

Andersen’s disease (GSD type IV) is characterized by the absence of the glycogen branching enzyme (GBE) which may lead to liver failure and death in childhood.

Milder mutations of GBE, such as p.Y329S in APBD, lead to smaller polyglucosan bodies, which do not disturb hepatocytes and most other cell types, merely accumulating in the sides of cells. In neurons and astrocytes, however, over time polyglucosan bodies plug the tight confines of axons and processes and lead to APBD.

Unlike Andersen’s disease, the onset is at late stage of adult life, where patients become symptomatic. These factors result in a difficult patient journey with misdiagnoses along the way. The majority of APBD patients are Ashkenazi Jewish bearing the p.Y329S mutation in the Gbe1 gene.

As APBD is an ultra-rare, adult disease with similar symptoms to more common diseases (Multiple Sclerosis, hereditary spastic paraplegia, Charcot-Marie-Tooth disease, adrenomyeloneuropathy, prostate hypertrophy in men, MSA, ALS), APBD is frequentlly misdiagnosed.

Therefore, although there are about 200 confirmed APBD cases worldwide, this is likely an underestimation. Recent market research suggested that the number of APBD patients is more likely to be higher.

The unmet need

Misdiagnosis Common​

Geneticdisorder with late age of onset
Similar symptoms to more common diseases

No good treatment options​

Symptomatic dietary management
Patients require easy administration

Ultra-rare disease​

Paucity of R&D
Small market

credit: Flaticon

While an effective cure for APBD is urgently needed, APBD is representative of the larger group of GSDs. GSDs are a varied group of 15 mostly incurable diseases with a combined prevalence of 1/10,000 births. Ranging from childhood liver disorders such as GSD1, through adolescent myoclonic epilepsies such as Lafora Disease (LD), and adult progressive neurodegenerative disorders such as APBD.

Glycogen Storage Diseases (GSD)

Glycogen Storage Diseases (GSD) frequency is c. 1:10,000 births, accumulated for all types of GSDs (>15 types), representing disorders that result in abnormal storage of glycogen.

All disorders are caused by an inborn errors of glucose and glycogen metabolism, which result from pathogenic variants in genes for virtually all of the proteins involved in glycogen synthesis, degradation, or regulation.

GSD 0a (MIM #240600, glycogen synthase 2 deficiency in liver)
GSD 0b (MIM #611556, muscle glycogen synthase deficiency)
GSD I (MIM #232200; GSD Ia,von Gierke disease*, glucose-6-phosphatase deficiency; GSD Ib due to a transport defect)
Lysosomal acid maltase deficiency (MIM #232300, acid alpha-glucosidase, Pompe disease*, GSD II)
Lysosome-associated membrane protein 2 (LAMP2) deficiency (MIM #300257, Danon disease, GSD IIb*)
GSD III (MIM #232400, glycogen debrancher deficiency), Cori'/Forbes' disease*
GSD IV (MIM #232500, glycogen branching enzyme deficiency), Andersen disease & APBD
GSD V (MIM #232600, McArdle disease, muscle phosphorylase deficiency)
GSD VI (MIM #232700, Hers' disease, liver phosphorylase deficiency)
GSD VII (MIM #232800, Tarui's disease, phosphofructokinase deficiency in muscle)
Phosphoglycerate kinase deficiency (MIM #311800)
GSD IX (phosphorylase kinase deficiency; IX a1, MIM #306000, formerly GSD VIII, alpha-2 subunit defect in liver; IXb, MIM #261750, beta subunit defect in liver; IXc, MIM #613027, gamma subunit defect in liver and muscle; IXd, MIM #300559, alpha subunit defect in muscle)
GSD X (MIM #261670, phosphoglycerate mutase deficiency)
GSD XI (MIM #612933; lactate dehydrogenase A [LDHA, MIM #150000] deficiency and lactate dehydrogenase B deficiency [LDHB, MIM #150100])
GLUT2 deficiency (MIM #138160; Fanconi-Bickel syndrome)
GSD XII (MIM #611881, aldolase A deficiency)
GSD XIII (MIM #612932, beta-enolase deficiency in muscle)
GSD XIV (MIM #612934, phosphoglucomutase 1 deficiency in muscle)
GSD XV (MIM #613507, glycogenin 1 deficiency in muscle)

Lysosomal Storage Diseases (LSD)

LSD frequency 1/5000-1/7500 births (group of ~70 different diseases)

Typically present in infancy and childhood, although adult-onset forms also occur.

Most LSDs have a progressive neurodegenerative clinical course; symptoms in other organ systems are frequent

Platt et al. 2018; Parenti et al. 2021

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