Adult-onset autosomal dominant leukodystrophy (ADLD) is a rare, slowly progressive, and fatal neurodegenerative disorder characterized by central nervous system white matter loss due to LMNB1 gene abnormalities encoding laminB1. However, not all LMNB1 mutations lead to ADLD. Currently, two genetic alterations have been identified in association with the pathogenesis of ADLD: LMNB1 gene tandem duplication and LMNB1 gene upstream deletions. We report a case of a 60-year-old man diagnosed with ADLD, with pyramidal tract dysfunction and autonomic abnormalities as the main clinical manifestations. MRI revealed bilateral symmetric high signal intensities in the white matter of the medulla oblongata, middle cerebellar peduncles, cerebral peduncle, periventricular white matter, centrum semi vale, and the pressure region of the corpus callosum. Whole exome sequencing results indicated 73.6Kb duplicate copy number variation signals in the 5q23.2 region of the proband's chromosome. The Multiplex ligation-dependent probe amplification (MLPA) experiment results indicate recurrent mutations across all exons (exon1-11) of the LMNB1 gene. This is the eighth ADLD pedigree from China. We conducted a literature review of all ADLD pedigrees in China and summarized the characteristics of Chinese patients with ADLD to raise awareness of ADLD disease.

Hutchinson-Gilford Progeria syndrome (HGPS) is a severe premature ageing disorder caused by a 50 amino acid truncated (Δ50AA) and permanently farnesylated lamin A (LA) mutant called progerin. On a cellular level, progerin expression leads to heterochromatin loss, impaired nucleocytoplasmic transport, telomeric DNA damage and a permanent growth arrest called cellular senescence. Although the genetic basis for HGPS has been elucidated 20 years ago, the question whether the Δ50AA or the permanent farnesylation causes cellular defects has not been addressed. Moreover, we currently lack mechanistic insight into how the only FDA-approved progeria drug Lonafarnib, a farnesyltransferase inhibitor (FTI), ameliorates HGPS phenotypes. By expressing a variety of LA mutants using a doxycycline-inducible system, and in conjunction with FTI, we demonstrate that the permanent farnesylation, and not the Δ50AA, is solely responsible for progerin-induced cellular defects, as well as its rapid accumulation and slow clearance. Importantly, FTI does not affect clearance of progerin post-farnesylation and we demonstrate that early, but not late FTI treatment prevents HGPS phenotypes. Collectively, our study unravels the precise contributions of progerin's permanent farnesylation to its turnover and HGPS cellular phenotypes, and how FTI treatment ameliorates these. These findings are applicable to other diseases associated with permanently farnesylated proteins, such as adult-onset autosomal dominant leukodystrophy.

Adult-onset autosomal dominant leukodystrophy (ADLD) is a rare genetic leukoencephalopathy caused by duplication of the lamin B1 gene (LMNB1) or LMNB1 upstream deletions. Neuronal intranuclear inclusion disease (NIID) is another leukoencephalopathy due to GGC repeat expansion in the 5'-untranslated region of the NOTCH2NLC gene. Here, we report two Chinese ADLD families with neuroimaging and clinical features mimicking NIID. We conducted detailed medical history inquiry, neurological examinations, and magnetic resonance imaging in the two families. Candidate gene sequencing and whole exome sequencing (WES) with copy number variation analysis were used to screen the genetic variations. The special points on the clinical and neuroimaging findings in the current families and differential diagnosis of ADLD with NIID are discussed. The two families presented with slowly progressive, multiple central nervous system symptoms, including spastic paraplegia, autonomic dysfunction, ataxia, deep sensory loss, and tremor. Clinical phenotypes were consistent within the family. Transient hypoglycemia and transient dilated pupils indicating autonomic dysfunctions were recorded for the first time in ADLD. Brain MRI showed band-like hyperintensities at the cortico-medullary junction on DWI, typical for NIID. Skin biopsy and genetic sequencing of the NOTCH2NCL gene did not support the diagnosis of NIID. Further whole exome sequencing (WES) identified the duplication mutation spanning the entire LMNB1 gene. The novel feature of transient hypoglycemia and dilated pupils broadens the spectrum of autonomic dysfunction in ADLD. Clinical manifestations and neuroimaging of ADLD can mimic NIID. Although ADLD is even rarer than NIID, the differential diagnosis of these two diseases should not be confused. LMNB1-related autosomal dominant leukodystrophy (ADLD) is a slowly progressive disorder of central nervous system white matter characterized by onset of autonomic dysfunction in the fourth to fifth decade, followed by pyramidal and cerebellar abnormalities resulting in spasticity, ataxia, and tremor. Autonomic dysfunction can include bladder dysfunction, constipation, postural hypotension, erectile dysfunction, and (less often) impaired sweating. Pyramidal signs are often more prominent in the lower extremities (e.g., spastic weakness, hypertonia, clonus, brisk deep tendon reflexes, and bilateral Babinski signs). Cerebellar signs typically appear at the same time as the pyramidal signs and include gait ataxia, dysdiadochokinesia, intention tremor, dysmetria, and nystagmus. Many individuals have sensory deficits starting in the lower limbs. Pseudobulbar palsy with dysarthria, dysphagia, and forced crying and laughing may appear in the seventh or eighth decade. Although cognitive function is usually preserved or only mildly impaired early in the disease course, dementia and psychiatric manifestations can occur as late manifestations. Affected individuals may survive for decades after onset. The diagnosis of LMNB1-related ADLD is established in a proband with suggestive clinical and MRI findings and either an LMNB1 duplication or (more rarely) a heterozygous deletion upstream of the LMNB1 promoter identified by molecular genetic testing. Treatment of manifestations: Treatment is symptomatic. For autonomic dysfunction: Neurogenic bladder may require management of urinary retention and/or urgency and recurrent urinary tract infection. Constipation may require good hydration, increased dietary fiber, stool softeners, and/or laxatives. Orthostatic hypotension can be minimized by pharmacologic intervention, compression stockings, physical therapy, and increased dietary salt. Erectile dysfunction is treated medically. Impaired sweating is managed with cool environment and attention to fever during infection. Spasticity may be treated with medications and physical therapy. Ataxia can be managed with strategies to minimize falls and increase strength, and adaptive equipment such as walkers or wheelchairs. Feeding difficulties can be managed with speech therapy and appropriate feeding interventions to assure adequate nutrition while preventing aspiration pneumonia. Surveillance: Routine assessment of: weight, nutrition, and feeding; pulmonary status (re possible recurrent pneumonia); bladder and erectile function; psychosocial well-being; and medications/doses to avoid iatrogenic polypharmacy. At least yearly assessment: by a neurologist for disease manifestations and progression; and by a physiatrist, orthopedist, physical therapist, and occupational therapist to address orthopedic, equipment, and functional needs. LMNB1-related ADLD is inherited in an autosomal dominant manner. To date, all individuals diagnosed with LMNB1-related ADLD whose parents have undergone molecular genetic testing have the disorder as the result of a large LMNB1 duplication (or a deletion upstream of LMNB1) inherited from an affected parent. Each child of an individual with LMNB1-related ADLD has a 50% chance of inheriting the LMNB1 duplication (or deletion upstream of LMNB1). Once the causative pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for LMNB1-related ADLD are possible.

Adult-onset autosomal dominant leukodystrophy (ADLD) is a lately described rare form of leukodystrophy with only one family report from China. As the only disease associated with increased lamina B1 encoded by LMNB1, ADLDs have different clinical presentations, ranging from autonomic to pyramidal tract and cerebellar ataxia. Here, we report a case of ADLD that presented with positional tremor as the initial symptom. T2-weighted brain MRI showed brain atrophy and diffuse high signal intensity of the cerebral white matter and the brain stem. The precise diagnosis was made by identification of the mutated gene. To the best of our knowledge, this is perhaps the first case report of ADLD presenting as tremor in China.