The diagnosis of hypophosphatasia in children as a multidisciplinary effort: an expert opinion.

Hypophosphatasia (HPP) is a rare genetic disorder in which pathogenic variants of the ALPL gene lead to a marked decrease of tissue non-specific alkaline phosphatase (TNSALP) activity. Although HPP is a systemic disorder, its clinical manifestations are more evident on bones, teeth, muscle and central nervous system. The clinical spectrum ranges from severe forms with extreme skeletal deformities, respiratory impairment, seizures, to very mild forms with onset in late adulthood and few clinical signs. The diagnosis can be suspected by measurement of TNSALP activity, but the insufficient awareness among health professionals and the lack of official guidelines are responsible for delayed diagnosis in children with HPP. The purpose of the current document is to provide an expert opinion directed at optimizing the diagnostic pathway of pediatric HPP. From April to December 2022, a multidisciplinary working group of 6 experts including two pediatric endocrinologists, a pediatric neurologist, a pediatric odontologist, a clinical geneticist, and a molecular biologist gathered in a series of periodic meetings to discuss the main issues related to the diagnosis of HPP in children and formalize an Expert Opinion statement. The experts agreed on a diagnostic trail that begins with the recognition of specific clinical signs, leading to biochemical analyses of TNSALP activity and vitamin B6 serum concentration. Very important are the neurological and dental manifestation of the disease that should be thoroughly investigated. The evaluation of TNSALP activity must consider sex and age variability and low activity must be persistent. Repeated blood measurements are thus necessary. The molecular analysis is then mandatory to confirm the diagnosis and for genetic counseling.

Neuroimaging Changes in Menkes Disease, Part 2.

This is the second part of a retrospective and review MR imaging study aiming to define the frequency rate, timing, imaging features, and evolution of gray matter changes in Menkes disease, a rare multisystem X-linked disorder of copper metabolism characterized by early, severe, and progressive neurologic involvement. According to our analysis, neurodegenerative changes and focal basal ganglia lesions already appear in the early phases of the disease. Subdural collections are less common than generally thought; however, their presence remains important because they might challenge the differential diagnosis with child abuse and might precipitate the clinical deterioration. Anecdotal findings in our large sample seem to provide interesting clues about the protean mechanisms of brain injury in this rare disease and further highlight the broad spectrum of MR imaging findings that might be expected while imaging a child with the suspicion of or a known diagnosis of Menkes disease.

Neuroimaging Changes in Menkes Disease, Part 1.

Menkes disease is a rare multisystem X-linked disorder of copper metabolism. Despite an early, severe, and progressive neurologic involvement, our knowledge of brain involvement remains unsatisfactory. The first part of this retrospective and review MR imaging study aims to define the frequency rate, timing, imaging features, and evolution of intracranial vascular and white matter changes. According to our analysis, striking but also poorly evolutive vascular abnormalities characterize the very early phases of disease. After the first months, myelination delay becomes evident, often in association with protean focal white matter lesions, some of which reveal an age-specific brain vulnerability. In later phases of the disease, concomitant progressive neurodegeneration might hinder the myelination progression. The currently enriched knowledge of neuroradiologic finding evolution provides valuable clues for early diagnosis, identifies possible MR imaging biomarkers of new treatment efficacy, and improves our comprehension of possible mechanisms of brain injury in Menkes disease.

Diagnostic imaging in 13 cases of Rasmussen's encephalitis: can early MRI suggest the diagnosis?

Rasmussen's encephalitis (RE) is a rare, progressive, chronic encephalitis characterised by drug-resistant epilepsy, progressive hemiparesis and mental impairment. It typically involves only one cerebral hemisphere, which becomes atrophic. We present neuroradiological findings in 13 children with RE. MRI was performed in all patients, fluorodeoxyglucose positron-emission tomography (PET) in three, Tc-99m hexamethylpropylenamine oxime single-photon emission computed tomography (SPECT) in two and proton MR spectroscopy ((1)HMRS) in two. MRI showed progression of the hemisphere atrophy, always prevalent in the region primarily involved (13 patients), spread of the abnormal signal in white matter (11) and cortex (10) and progression of atrophy of the head of the caudate nucleus (nine). Associated secondary changes were: atrophy of the contralateral cerebellar hemisphere (in four patients), the ipsilateral hippocampus (in five) and the brain stem (in five). The earliest CT and MRI abnormalities, seen between 1 day and 4 months after the first seizure (in 12 patients examined, nine of whom had MRI) in one cerebral hemisphere included: high signal on T2-weighted images in the cortex (seven patients) and white matter (nine), cortical atrophy usually involving the frontoinsular region, with mild or severe enlargement of the lateral ventricle (eight) and moderate atrophy of the head of the caudate nucleus (seven). Cortical swelling in the early stage of the disease was recognisable only in two patients. PET revealed hypometabolism, SPECT decreased perfusion, and (1)HMRS reduction of N-acetylaspartate in the affected hemisphere. PET and SPECT were usually performed in the late stages and did not provide specific findings. MRI thus demonstrates the progression of RE and may suggest the diagnosis in the early stages, often before the appearance of neurological deficits. Early diagnosis of RE may be crucial for selecting patients for aggressive medical therapy or major surgical interventions such as hemispherectomy.

Experience with immunomodulatory treatments in Rasmussen's encephalitis.

The authors investigated immunomodulatory treatments in 15 patients with Rasmussen encephalitis (RE) (14 with childhood and one with adolescent onset RE). Positive time-limited responses were obtained in 11 patients using variable combinations of corticosteroids, apheresis, and high-dose IV immunoglobulins. Although surgical exclusion of the affected hemisphere is the only treatment that halts disease progression, immunomodulation can be considered when early surgery is not feasible, in late-onset patients with slower disease progression, and in the few cases of bilateral disease.

Rasmussen's encephalitis: early characteristics allow diagnosis.

OBJECTIVE: To identify early manifestations of Rasmussen encephalitis (RE) that can prompt early and reasonably secure diagnosis, allowing medical or surgical therapies at an early stage when they may be more effective in slowing the disease. METHODS: The authors studied 12 patients with clinical and neuropathologic diagnosis of RE, followed from disease onset, assessing clinical history, imaging, and EEG and focusing on early characteristics. Anti-GluR3 antibody assays were also considered in 11 patients. RESULTS: By 4 months from first symptoms, all cases had 1) refractory focal seizures with a predominant motor component, 2) slow focal activity on EEG contralateral to the motor manifestations, and 3) focal contralateral white matter hyperintensity with insular cortical atrophy on neuroimaging. Less constant or later findings were epilepsia partialis continua, oligoclonal bands, and serum anti-GluR3 antibodies. CONCLUSIONS: The association of partial seizures with focal EEG and neuroimaging changes allows a tentative diagnosis of RE 4 to 6 months after first symptoms.