Homozygous mutations in the gene CLN1 typically result in infantile-onset neuronal ceroid lipofuscinosis, a severe progressive neurological disorder with early death. The gene CLN1 encodes the enzyme palmitoyl protein thioesterase (PPT1), which is involved in lysosomal degradation of S-fatty acylated proteins. Cysteamine bitartrate (Cystagon) has been shown to reduce the storage material in PPT1 deficient cells. We report the results of a 7-year, open label, nonrandomized trial using Cystagon in four individuals with juvenile-onset NCL resulting from milder CLN1 mutations. The Cystagon doses were gradually increased with the goal of achieving 50 mg/kg bodyweight. The disease progression was monitored with parental questionnaires in four treated individuals and five untreated controls with the same CLN1 mutations. Mononuclear leukocytes from the treated individuals were examined for submicroscopic lysosomal storage inclusions. Cystagon treatment resulted in decreased storage material in peripheral leukocytes of the treated individuals. No severe side effects were noted. An allergic rash occurred in one of the individuals that required a dose reduction. The treatment did not result in overall attenuation of the disease progression. Slower progression of the disease was observed in two of the individuals when they were analyzed separately. However, slower progression in these individuals was also observed prior to starting the treatment. This effect may have been due to the higher Cystagon dose achieved in this group, but it could also have been coincidental. The apparent lack of toxicity of Cystagon may warrant further Cystagon trials in infantile NCL, possibly in conjunction with other developing therapies.

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Substrate Reduction Therapy in Four Patients with Milder CLN1 Mutations and Juvenile-Onset Batten Disease Using Cysteamine Bitartrate

Charcot-Marie-Tooth disease (CMTD) is an uncommon progressive neuromuscular disorder of the peripheral nervous system and primarily leads to distal extremity weakness and sensory deficits. Frequently, affected patients manifest pes cavus, drop foot, and digit contractures that may pose significant challenges in ambulation and grasping objects. Although there are numerous articles of this syndrome in the medical literature, there is a limited number of dental publications. The objective of this article is to review the general and head and neck/oral and maxillofacial features of CMTD. General guidelines for dental management are also provided. 

Review of general and head and neck/oral and maxillofacial features of Charcot-Marie-Tooth disease and dental management considerations

Natural history variations for neuronal ceroid lipofuscinosis type 2: In support of newborn screening

A 9-yr 8-mo-old right-handed female presented with a history of gait difficulties, which first became apparent at age 9 mo of age, along with slurred speech and hand tremors while holding a tray. Her past medical history was significant for global developmental delay, and she was attending fourth grade special education classes. On examination, she had an ataxic gait, dysarthria, absent deep tendon reflexes, and flexor plantar responses. There were no signs of optic atrophy or hearing loss. Nerve conduction studies were consistent with an axonal neuropathy. A fascicular sural nerve biopsy showed a marked decrease of myelinated fibers larger than 6 µm in diameter as compared with an age-matched control. By electron microscopy, clusters of degenerating axonal mitochondria in both myelinated and unmyelinated fibers were frequently found. Whole-exome sequencing revealed a heterozygous c.314C > T (p.Thr105Met) missense variant in MFN2 in the patient but not in her mother. The father was unavailable for testing. The phenotypes with MFN2 variants can be quite variable, including intellectual disability, optic atrophy, auditory impairment, spinal atrophy with or without hydromyelia, and hydrocephalus. We report here that early onset ataxia with intellectual disability can also be associated with MFN2-related Charcot-Marie-Tooth, Type 2A2A diagnosis, the most common type of autosomal dominant axonal neuropathy.

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Early-onset cerebellar ataxia in a patient with CMT2A2.

Diagnosis of late-infantile neuronal ceroid lipofuscinosis using dried blood spot-based assay for TPPI enzyme activity: TPPI diagnostic assay from DBS.

A case study conducted for 8 years from 2003 to 2010 with a one-year temporary interruption in 2008, revealed that Cystagon seemed to be a potential treatment agent for neuronal ceroid lipofuscinosis (NCL), also known as Batten disease. As the dosage of Cystagon increased, the numbers of lymphocytes containing granular osmiophilic dense deposits (GROD, one of the pathological hallmarks) decreased. When the dosage of Cystagon reached between 47 and 50 mg/kg body weight, the numbers of lymphocytes containing GRODs plateaued. Our 8-year follow-up suggests that Cysteamine (Cystagon) treatment may be a potentially promising agent for NCL treatment. It might be more accurate to say the Cystagon has improved some of the clinical manifestations, the quality of this patient’s life, his behavior and functioning, but did not affect the overall disease progression. The parents also felt that Cystagon decreased the “psychotic manisfestation” – auditory and visual hallucination. Further studies with more patients using this medication are needed.

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Maureen Gavin

Papers

Early-onset cerebellar ataxia in a patient with CMT2A2.

Diagnosis of late-infantile neuronal ceroid lipofuscinosis using dried blood spot-based assay for TPPI enzyme activity: TPPI diagnostic assay from DBS.

Cystagon Treatment for Neuronal Ceroid Lipofuscinosis: An 8-Year Case Study