Radhika Dhamija

22q11.2 deletion syndrome presenting with early-onset Parkinson's disease.

Velocardiofacial syndrome, also known as DiGeorge syndrome, is a multisystem genetic disorder caused by microdeletion of 3.0 megabases (Mb) of DNA on the long arm of chromosome 22. Recently, 22q11.2 deletion syndrome (22q11.2DS) has been recognized as a potential risk factor for the development of Parkinson’s disease (PD). We report on a patient with 22q11.2DS who was identified when he presented with early-onset PD. A 37-year-old man presented for PD treatment. He first noted a right rest tremor at age 30. He subsequently developed a similar tremor in his left hand with noted difficulty manipulating objects and utensils. He was diagnosed with PD at age 31 and had improvement with levodopa initiation. Over time, he required increasing doses of L-dopa to manage his motor symptoms and developed motor fluctuations and dyskinesias. His medications were carbidopa/L-dopa 25/ 100 mg, 1 tablet 5 times a day; entacapone 200 mg, 1 tablet 4 times a day; and amantadine 100 mg, 1 tablet 3 times a

Evolution of brain lesions in a patient with TREX1 cerebroretinal vasculopathy.

A 44-year-old woman with a history of retinal vasculopathy presented with headaches and hemiparesis. MRI brain showed a right frontal peripherally enhancing mass with surrounding edema (figure 1) thought to represent a malignant glioma; however, pathology showed necrosis with reactive gliosis but no evidence of neoplasm (figure 2). Family history was significant for multiple relatives with similar lesions on head MRIs suspicious for neoplasm but excluded by biopsy. An underlying familial leukoencephalopathy was suspected, and a novel heterozygous nonsense mutation c.1359G>T; p.Glu285* was identified in TREX1, in which C-terminal frameshift mutations cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.1

Paraspinal neurofibromas and hypertrophic neuropathy in Noonan syndrome with multiple lentigines

Background Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD syndrome, is an autosomal-dominant disorder characterised by lentigines, EKG abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, growth retardation and deafness. There is significant clinical overlap between NSML and other disorders that result from dysregulated rat sarcoma/mitogen-activated protein kinase pathway (RASopathies). Except for neurofibromatosis type 1, other RASopathies are not known to be typically associated with neurogenic tumours. Methods and results We evaluated patients from three families with pigmentary skin lesions, progressive neuropathy, enlarged nerves, massive burden of paraspinal tumours (neurofibroma was confirmed in one patient) and a clinical diagnosis of NSML. All patients had a mutation in the protein tyrosine phosphatase catalytic domain of the PTPN11 gene; two unrelated patients had the p.Thr468Met mutation, while the family consisting of two affected individuals harboured the p.Thr279Cys mutation. Molecular analysis performed on hypertrophic nerve tissue did not disclose a second somatic hit in NF1, PTPN11, NF2 or SMARCB1 genes. Conclusions Neurogenic tumours and hypertrophic neuropathy are unusual complications of NSML and may be an under-recognised manifestation that would warrant surveillance. Our observation may also have implications for other disorders caused by RAS-pathway dysregulation.

Teaching NeuroImages: Neurocutaneous melanosis

A 3-month-old boy presented with a giant congenital melanocytic nevus involving his back. He was developing normally with no neurologic symptoms. Brain MRI demonstrated a T1-bright lesion in right amygdala without necrosis, hemorrhage, edema, or enhancement (figure). MRI spine was normal. The imaging findings in the clinical setting are consistent with a diagnosis of neurocutaneous melanosis.

Pathogenic Variant in ACTB, p.Arg183Trp, Causes Juvenile-Onset Dystonia, Hearing Loss, and Developmental Delay without Midline Malformation

ACTB encodes the β-actin, and pathogenic variations in this gene have typically been associated with Baraitser-Winter cerebrofrontofacial syndrome, a congenital malformation syndrome characterized by short stature, craniofacial anomalies, and cerebral anomalies. Here, we describe the third case with the p.Arg183Trp variant in ACTB causing juvenile-onset dystonia. Our patient has severe, intractable dystonia, developmental delay, and sensorineural hearing loss, besides hyperintensities in the caudate nuclei and putamen on the brain MRI, which is a distinct but overlapping phenotype with the previously reported case of identical twins with the same alteration in ACTB.

Teaching NeuroImages: Intracranial hypotension in a patient with Marfan syndrome

An 18-year-old man with Marfan syndrome and migraine headaches presented with acute worsening of headaches with postural changes following spinal fusion surgery for scoliosis. Lumbar spine MRI done before surgery showed diffuse dural ectasia (figure 1). Brain MRI after surgery showed distended transverse and sagittal dural venous sinuses1 and an enlarged pituitary gland suggesting intracranial hypotension (figure 2). He was treated conservatively with rest, fluids, and caffeine. Patients with Marfan syndrome frequently have dural ectasia2 and are at risk of CSF leaks after spinal surgery leading to intracranial hypotension. Our case highlights subtle changes on brain MRI suggesting intracranial hypotension.

GNAO1-Associated Movement Disorder

Keywords: chorea; whole-exome sequencing; guanine nucleotide-binding protein; α-activating activity polypeptide O (GNAO1)

A Patient With DNMT1 Gene Mutation Presenting With Polyneuropathy, Hearing Loss, and Personality Changes

OBSERVATION A Patient With DNMT1 Gene Mutation Presenting With Polyneuropathy, Hearing Loss, and Personality Changes Hereditary sensorineural hearing loss can be syndromic or nonsyndromic. Genetic causes of hearing loss must be distinguished from acquired causes for purposes of genetic counseling. Next-generation sequencing (NGS) panels are now used widely in clinical settings to try to identify genetic causes of hearing loss. Report of a Case | A woman in her 40s was initially referred to our neuromuscular clinic for polyneuropathy and hearing loss. On examination, she was inappropriately happy and indifferent. Her neurologic examination was notable for clinically significant sensory loss to pinprick, vibration, and position sensation distally in the upper and lower extremities and symmetric hyporeflexia. A nerve conduction study showed severe sensory neuropathy, with absent potentials in upper and lower extremity. Common causes of neuropathy, such as inflammatory, vitamin deficiencies, diabetes mellitus, alcoholism, and paraneoplastic and immunemediated causes, were considered and excluded by appropriate studies. An otolaryngology consultation was obtained for her associated hearing loss. She reported a 5-year history of hearing loss and denied having significant noise exposure or family history of hearing loss. A hearing test performed at onset of her hearing loss demonstrated right-ear mid-frequency moderate sensorineural hearing loss between the frequencies of 500 and 2000 Hz. In the left ear there was moderately severe midand high-frequency hearing loss. Asymmetry between the ears was noted in the high frequencies between 1500 and 4000 Hz with the left ear having 30-dB HL worse hearing loss. (Figure 1A) Progressive and asymmetric hearing loss in adulthood led to consideration of autoimmune inner ear disease or a retrocochlear lesion. Results from a workup for autoimmune inner ear disease were negative. Magnetic resonance imaging of the head was negative for a retrocochlear lesion but showed cerebellar atrophy (Figure 2). At the time of her initial hearing test, the audiometric configuration in her right ear demonstrated mid-frequency sensorineural hearing loss or “cookie

Detection of gonadal mosaicism in Hartsfield syndrome by next generation sequencing.

Detection of Gonadal Mosaicism in Hartsfield Syndrome by Next Generation Sequencing Yong Shi, Radhika Dhamija, Catherine Wren, Xiangling Wang, Dusica Babovic-Vuksanovic, and Elaine Spector* Department of Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine/Molecular Genetics Laboratory, Aurora, Colorado Departments of Neurology and Pediatrics, University of Virginia, Charlottesville, Virginia Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota

Diagnostic NGS for Severe Neuromuscular Disorders

Investigators from the University of Western Australia report the diagnostic yield of performing next generation sequencing (NGS; whole exome and targeted capture of 277 neuromuscular genes) in a heterogenous cohort of patients with neuromuscular disorders (NMD) presenting at or before birth.