Whole exome sequencing has just established an adolescent male as having hereditary diffuse leukoencephalopathy with spheroids.
Other recent whole exome sequencing discoveries recently: Sanjad-Sakati syndrome, Bohring-Opitz, EEF1A2, SCN8A, SCN9A, NDUFA1, GRIN1, ATP2B3, KIF1A, MAGEL2 (see MAGEL2 gene mutation 6/5/15).
My geneticist colleague met with the parents of an adolescent male with profound neurological handicap to tell them of the diagnosis of Bohring-Opitz síndrome. She indicated the parents were ecstatic. Now reflect. The diagnosis did not change the patient in any way. He continues to have profound neurological handicap. His therapies are not altered. The parents' situation no longer involves a need for consideration of reproductive risk. However, just having a diagnosis seems to have a strong cathartic effect.
A colleague wrote: I have run into this phenomenon many times. People feel better with an answer or even just a name for their problem. I would feel better if I had an answer for my problem.
ReplyDeleteDiagnosis by Medline
ReplyDeleteMeyer-Ohlendorf M, Braczynski A, Al-Qaisi O, Gessler F, Biskup S, Weise L,
Steinbach JP, Wagner M, Mittelbronn M, Bähr O. Comprehensive diagnostics in a
case of hereditary diffuse leukodystrophy with spheroids. BMC Neurol. 2015 Jul
4;15(1):103.
Abstract
BACKGROUND:
Hereditary diffuse leukodystrophy with spheroids is a rare type of leukoencephalopathy. Mutations in the colony stimulating factor 1 receptor have recently been identified to be the cause of this microgliopathy. Clinical and radiological presentation can often misguide physicians during the diagnosis of patients with this underdiagnosed disease.
CASE PRESENTATION:
We present a 29 year-old woman with a rapid course of hereditary diffuse leukodystrophy with spheroids. She mainly showed cognitive impairment and severe motor dysfunctions. Her MRI showed spotted and confluent hyperintensities of the white matter on T2-weighted images involving the corticospinal tract as well as the corpus callosum. Further, those lesions showed striking restricted diffusion. As this restricted diffusion in all areas showing signs of leukoencephalopathy was so impressive we searched Medline for these terms and got hereditary diffuse leukodystrophy with spheroids as one of the first results. After a comprehensive diagnostic workup and exclusion of other leukoencephalopathies, stereotactic biopsy and genetic testing confirmed the diagnosis.
CONCLUSION:
This case points out at two important features of hereditary diffuse leukodystrophy with spheroids being spotted and/or confluent leukoencephalopathy with areas of restricted diffusion. This might help to identify more patients with this underdiagnosed disease. Moreover, the rapid clinical course in our patient raises the question whether the relatively pronounced areas of restricted diffusion are indicative of a more acute progression of the disease.
Also: "Notably, a Medline search with the two most conspicuous features of this case suggested the diagnosis of HDLS before biopsy or genetic testing were done...
Nonetheless, the stereotactic biopsy was performed and corroborated the diagnosis. Finally, the histological diagnosis was confirmed by the genetic testing."
The patient has diffuse bony abnormalities described as metaphyseal dysplasia.
ReplyDeleteFrom an Xray report: "Erlenmeyer flask deformities seen in the bilateral femurs. The bilateral proximal tibial metadiaphysis are also abnormally widened. Findings can be seen in Gaucher disease, Niemann-Pick disease, and thalassemia. Bilateral genu valgum is present.”
From a spine MRI report: "Pronounced concavity of the endplates throughout the spine but most pronounced in the thoracic and lumbar spine. No global vertebral body collapse. Overall vertebral body heights are maintained. Alignment is normal. Normal marrow signal. Disc heights are exaggerated. No posterior or foraminal herniation. Normal facets.”
A geneticist colleague indicated, “I have shared his clinical info and skeletal survey images with Dr Hoover Fong and another skeletal dysplasia experts and they haven’t seen anything like this.”
This issue is distinct from the patient's diagnosis of hereditary diffuse leukoencephalopathy with spheroids and has remained unexplained, even after whole exome sequencing.
A more complete skeletal survey report
ReplyDeleteFINDINGS: There is sclerosis and cortical thickening seen in the calvarial vault, and
particularly at the skull base. Additionally, there is undertubulation of long bones,
at the proximal aspect of the humeri and distal aspect of the femora particularly but
also at the proximal and distal aspect of the tibia, and the distal aspect of the
radius and ulna. At the other end of the long bone diaphyses, there is pronounced
cortical thickening, obscuring the medullary cavity, with otherwise tapered appearance
of this portion of the bone. Mild negative ulnar variance are present bilaterally in
the forearms.
Cortical thickening is noted in the distal aspect of the phalanges of of both hands
and in the proximal 2nd through 5th metacarpals and distal 1st metacarpal, with
similar findings in the bilateral feet. Mild bilateral hallux valgus deformities
present. The proximal metacarpals are tapered, as are the distal humeri bilaterally.
There is also dysplasia of the vertebral bodies, with endplate compression and wedging
posteriorly, most pronounced in the thoracic and lumbar spine, with cortical
thickening noted in the spinous processes of the cervical spine. The ribs also appear
somewhat flared anteriorly, and cortical thickening is noted in the pelvis in the
iliac bones just cephalad to the acetabula bilaterally. Remote, healed midshaft
fracture of the right femur with prior instrumentation noted, along with screw tracks
the proximal tibias and distal left femur.
IMPRESSION: Unusual sclerosing skeletal dysplasia, as above with features that suggest
craniometaphyseal dysplasia, but with other unique features including a vertebral
dysplasia with posterior wedging/thinning, negative ulnar variance, and the tapered
appearance of the long bones, phalanges, metatarsals, and metacarpals in regions of
cortical thickening, limiting definitive diagnosis.
A colleague wrote: I would not be so quick to dismiss the role of CSF1R in the skeletal problems of your patient, since, as the attached diagram shows (diagram available on request-gbreningstall@gillettechildrens.com), PIK3R1 and CBL have important interactions with CSF1R, and there are numerous publications on the combined actions of PIK3R1 and CBL on bone morphogenesis through regulation of osteoclast function. Therefore, certain mutations in CSF1R might have dominant-negative effects on PIK3R1-CBL interaction. It seems reasonable also to speculate that patients with a disorder that is manifest principally in the brain might never have had a below-neck skeletal series, which might reveal a milder, clinically inapparent skeletal phenotype in many or all patients. There are similar protein-protein interaction phenomena in metabolic disorders I deal with. For example, I now find that the strange and variable phenotype of desmosterolosis probably has nothing to do with sterol metabolism but, instead, reflects the loss of binding sites on DHCR24 for two other proteins.
ReplyDeleteAnother colleague wrote: I hypothesize that if these adult patients were symptomatic during an earlier phase of bone development, they theoretically could have bone disease. I wonder if tissue specific expression of this gene has been studied.
Only strange thing then, would be why this individual is symptomatic much earlier than those reported. Only one other nonsense mutation in the group and this one was later on. Perhaps there is some key functional site between our patient's nonsense mutation and the adult's nonsense mutation. That might explain our patient's earlier onset.
This colleague cited: Thomas K, Huang CS, Gutknecht MF, Botchwey EA, Bouton AH. Regulation of osteoclast structure and function by FAK family kinases. J Leukoc Biol. 2012 Nov;92(5):1021-8.
More thoughts from a colleague: EST databases have their limitations, but Unigene shows that expression of CSF1R in bone is relatively strong (stronger than in brain) (diagram aavailable on request). However, if the apparent defect in osteoblast/osteoclast function were secondary to loss of interaction with the one of the associated signaling proteins, then skeletal involvement might be very mutation-specific or mutation-type specific. Shopping around for other cases that have had or could have bone x-rays done might show something surprising. I think of the number of patients with neutropenia in years past in whom the diagnosis of Shwachman-Diamond syndrome was missed because no skeletal films were done or because the studies were done at a young age when the metaphyseal dysplasia can be subtle. My instincts tell me to put my money on the skeletal phenotype being caused by the CSF1R mutation.
ReplyDeleteOur patient presented at 14 years of age after developing a left hemiparesis. See:
ReplyDeleteKitani-Morii F, Kasai T, Tomonaga K, Saito K, Mizuta I, Yoshioka A, Nakagawa
M, Mizuno T. Hereditary diffuse leukoencephalopathy with spheroids characterized
by spastic hemiplegia preceding mental impairment. Intern Med.
2014;53(12):1377-80.
Abstract
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a young-adult-onset autosomal dominant white matter disease characterized by progressive cognitive dysfunction. We herein report the case of a 20-year-old woman who developed spastic hemiplegia. Brain magnetic resonance imaging revealed increased bilateral T2 signal intensity and bright diffusion-weighted imaging signals with a low apparent diffusion coefficient within the frontoparietal white matter. The lesion gradually expanded for over one year. The patient was initially diagnosed with multiple sclerosis (MS); however, she did not respond to immunosuppressive therapy. DNA sequencing showed a heterozygous c.2381T>C mutation in colony-stimulating factor 1 receptor. HDLS with a pure motor phenotype is sometimes difficult to differentiate from MS.
A boy with Lennox-Gastaut syndrome, hypotonia and global developmental handicaps pursued a neurodegenerative course and died in hospice circumstances at just over 4 years of age. Whole exome sequencing established him to have an abnormality in the EEF1A2 gene.
ReplyDeleteSee: Nakajima J, Okamoto N, Tohyama J, Kato M, Arai H, Funahashi O, Tsurusaki Y, Nakashima M, Kawashima H, Saitsu H, Matsumoto N, Miyake N. De novo EEF1A2 mutations in patients with characteristic facial features, intellectual disability, autistic behaviors and epilepsy. Clin Genet. 2014 Apr 3.
Abstract
Eukaryotic elongation factor 1, alpha-2 (eEF1A2) protein is involved in protein synthesis, suppression of apoptosis, and regulation of actin function and cytoskeletal structure. EEF1A2 gene is highly expressed in the central nervous system and Eef1a2 knockout mice show the neuronal degeneration. Until now, only one missense mutation (c.208G > A, p.Gly70Ser) in EEF1A2 has been reported in two independent patients with neurological disease. In this report, we described two patients with de novo mutations (c.754G > C, p.Asp252His and c.364G > A, p.Glu122Lys) in EEF1A2 found by whole-exome sequencing. Common clinical features are shared by all four individuals: severe intellectual disability, autistic behavior, absent speech, neonatal hypotonia, epilepsy and progressive microcephaly. Furthermore, the two patients share the similar characteristic facial features including a depressed nasal bridge, tented upper lip, everted lower lip and downturned corners of the mouth. These data strongly indicate that a new recognizable disorder is caused by EEF1A2 mutations.