Lysosomal storage disease associated with a CNP sequence variant in Dalmatian dogs

A progressive neurological disorder was identified in purebred Dalmatian dogs. The disease is characterized by anxiety, pacing and circling, hypersensitivity, cognitive decline, sleep disturbance, loss of coordination, loss of control over urination and defecation, and visual impairment. Neurological signs first became apparent when the dogs were approximately 18 months of age and progressed slowly. Two affected littermates were euthanized at approximately 7 years, 5 months and 8 years, 2 months of age due to the severity of neurological impairment. The mother of the affected dogs and four other relatives exhibited milder, later-onset neurological signs. Pronounced accumulations of autofluorescent intracellular inclusions were found in cerebral cortex, cerebellum, optic nerve, and cardiac muscle of the affected dogs. These inclusions co-localized with immunolabeling of the lysosomal marker protein LAMP2 and bound antibodies to mitochondrial ATPase subunit c, indicating that the dogs suffered from a lysosomal storage disease with similarities to the neuronal ceroid lipofuscinoses. Ultrastructural analysis indicated that the storage bodies were surrounded by a single-layer membrane, but the storage granules were distinct from those reported for other lysosomal storage diseases. Whole genome sequences, generated with DNA from the two euthanized Dalmatians, both contained a rare, homozygous single-base deletion and reading-frame shift in CNP which encodes the enzyme CNPase (EC 3.1.4.37). The late-onset disease was exhibited by five of seven related Dalmatians that were heterozygous for the deletion allele and over 8 years of age, whereas none of 16 age-matched reference-allele homozygotes developed neurologic signs. No CNPase antigen could be detected with immunohistochemical labeling in tissues from the dogs with the earlier-onset disorder. Similar to the later-onset Dalmatians, autofluorescent storage granules were apparent in brain and cardiac tissue from transgenic mice that were nullizygous for Cnp. Based on the clinical signs, the histopathological, immunohistochemical, ultrastructural, and molecular-genetic findings, and the finding that nullizygous Cnp mice accumulate autofluorescent storage granules, we propose that the earlier-onset Dalmatian disorder is a novel lysosomal storage disease that results from a loss-of-function mutation in CNP and that shares features characteristic of the neuronal ceroid lipofuscinoses. That the later-onset disorder occurred only in dogs heterozygous for the CNP deletion variant suggests that this disorder is a result of the variant allele’s presence

HIV/AIDS, declining family resources and the community safety net

Families play central roles in the HIV/AIDS pandemic, caring for both orphaned children and the ill. This extra caregiving depletes two family resources essential for supporting children: time and money. We use recent data from published studies in sub-Saharan Africa to illustrate deficits and document community responses. In Botswana, parents caring for the chronically ill had less time for their preschool children (74 versus 96 hours per month) and were almost twice as likely to leave children home alone (53% versus 27%); these children experienced greater health and academic problems. Caregiving often prevented adults from working full time or earning their previous level of income; 47% of orphan caregivers and 64% of HIV/AIDS caregivers reported financial difficulties due to caregiving. Communities can play an important role in helping families provide adequate childcare and financial support. Unfortunately, while communities commonly offer informal assistance, the value of such support is not adequate to match the magnitude of need: 75% of children's families in Malawi received assistance from their social network, but averaging only US$81 annually. We suggest communities can strengthen the capacity of families by implementing affordable quality childcare for 0–6 year olds, after-school programming for older children and youth, supportive care for ill children and parents, microlending to enhance earnings, training to increase access to quality jobs, decent working conditions, social insurance for the informal sector, and income and food transfers when families are unable to make ends meet

A homozygous ADAMTS2 nonsense mutation in a Doberman Pinscher dog with Ehlers Danlos syndrome and extreme skin fragility

An eight-week old Doberman Pinscher was diagnosed with Ehlers Danlos syndrome based on the dog's hyper-mobile carpal, tarsal and stifle joints and abnormal skin. The skin was loose and hyper-elastic with several wounds and large atrophic scars. The dog was euthanized after a severe degloving injury from minimal trauma. A whole-genome sequence, generated with DNA from the dog's blood, contained a rare, homozygous C-to-T transition at position 2408978 on chromosome 11. This transition is predicted to alter the ADAMTS2 transcript (ADAMTS2:c.769C>T) and encode a nonsense mutation (p.Arg257Ter). Biallelic ADAMTS2 mutations have caused a type of Ehlers Danlos syndrome known as dermatosparaxis in other species

Consequences of HIV for children: avoidable or inevitable?

The HIV/AIDS epidemic has many serious consequences for children. These consequences are, however, rarely inevitable. Families can provide a protective barrier that deflects blows, or minimises their impact and a supportive nurturing environment that can help children recover from harm. If strong enough, and with sufficient access to quality services and support from communities, families can reduce the impacts of HIV/AIDS on children to negligible levels in most areas of impact. It is apparent that the impacts felt by children are not simply unfortunate, inevitable consequences of this epidemic. A strong and supported family with good access to quality services can deflect almost all of the impact. It is as a result of an interaction of the context of poverty, which weakens families, and a failure to adequately respond, that impacts are felt by children

Food meanings in HIV and AIDS caregiving trajectories: Ritual, optimism and anguish among caregivers in Lesotho

The article describes the caregiving responsibility to provide food for chronically ill family members and the meanings attached to food and eating when ill created stress for family caregivers. The results come from a qualitative phenomenological study using in-depth interviews with 21 family caregivers of chronically ill HIV and AIDS patients in one district in Lesotho. Analysis of the interview data showed that the caregivers attached profound meanings to food and feeding care recipients. Their perceptions about food as part of family life and caring, the role of food and eating in curbing disease progression, the link between food and medical efficacy and the link between food and life led to ritualised behaviour around food, and moments of optimism and anguish in caregiving. Patients’ behaviour in relation to food was in most instances inconsistent with the caregivers’ goals, thus leading this aspect of caregiving to induce stress. Services intended to support home-based caregivers and patients could contribute to the reduction of stress associated with food through suitably tailored food assistance and professional support to caregivers to enhance their competences and understanding of the dynamics of food intake as AIDS progressed

Multiple stressors in Southern Africa: the link between HIV/AIDS, food insecurity, poverty and children's vulnerability now and in the future

Several countries in Southern Africa now see large numbers of their population barely subsisting at poverty levels in years without shocks, and highly vulnerable to the vagaries of the weather, the economy and government policy. The combination of HIV/AIDS, food insecurity and a weakened capacity for governments to deliver basic social services has led to the region experiencing an acute phase of a long-term emergency. “Vulnerability” is a term commonly used by scientists and practitioners to describe these deteriorating conditions. There is particular concern about the “vulnerability” of children in this context and implications for children's future security. Through a review of literature and recent case studies, and using a widely accepted conceptualisation of vulnerability as a lens, we reflect on what the regional livelihoods crisis could mean for children's future wellbeing. We argue that an increase in factors determining the vulnerability of households — both through greater intensity and frequency of shocks and stresses (“external” vulnerability) and undermined resilience or ability to cope (“internal” vulnerability) — are threatening not only current welfare of children, but also their longer-term security. The two specific pathways we explore are (1) erosive coping strategies employed by families and individuals; and (2) their inability to plan for the future. We conclude that understanding and responding to this crisis requires looking at the complexity of these multiple stressors, to try to comprehend their interconnections and causal links. Policy and programme responses have, to date, largely failed to take into account the complex and multi-dimensional nature of this crisis. There is a misfit between the problem and the institutional response, as responses from national and international players have remained relatively static. Decisive, well-informed and holistic interventions are needed to break the potential negative cycle that threatens the future security of Southern Africa's children

Barriers and incentives to orphan care in a time of AIDS and economic crisis: a cross-sectional survey of caregivers in rural Zimbabwe

BACKGROUND: Africa is in an orphan-care crisis. In Zimbabwe, where one-fourth of adults are HIV-positive and one-fifth of children are orphans, AIDS and economic decline are straining society's ability to care for orphans within their extended families. Lack of stable care is putting thousands of children at heightened risk of malnourishment, emotional underdevelopment, illiteracy, poverty, sexual exploitation, and HIV infection, endangering the future health of the society they are expected to sustain. METHODS: To explore barriers and possible incentives to orphan care, a quantitative cross-sectional survey in rural eastern Zimbabwe asked 371 adults caring for children, including 212 caring for double orphans, about their well-being, needs, resources, and perceptions and experiences of orphan care. RESULTS: Survey responses indicate that: 1) foster caregivers are disproportionately female, older, poor, and without a spouse; 2) 98% of non-foster caregivers are willing to foster orphans, many from outside their kinship network; 3) poverty is the primary barrier to fostering; 4) financial, physical, and emotional stress levels are high among current and potential fosterers; 5) financial need may be greatest in single-orphan AIDS-impoverished households; and 6) struggling families lack external support. CONCLUSION: Incentives for sustainable orphan care should focus on financial assistance, starting with free schooling, and development of community mechanisms to identify and support children in need, to evaluate and strengthen families' capacity to provide orphan care, and to initiate and support placement outside the family when necessary

A mutation in the Warburg syndrome gene, <i>RAB3GAP1</i>, causes a similar syndrome with polyneuropathy and neuronal vacuolation in Black Russian Terrier dogs

AbstractAn autosomal recessive disease of Black Russian Terriers was previously described as a juvenile-onset, laryngeal paralysis and polyneuropathy similar to Charcot Marie Tooth disease in humans. We found that in addition to an axonal neuropathy, affected dogs exhibit microphthalmia, cataracts, and miotic pupils. On histopathology, affected dogs exhibit a spongiform encephalopathy characterized by accumulations of abnormal, membrane-bound vacuoles of various sizes in neuronal cell bodies, axons and adrenal cells. DNA from an individual dog with this polyneuropathy with ocular abnormalities and neuronal vacuolation (POANV) was used to generate a whole genome sequence which contained a homozygous RAB3GAP1:c.743delC mutation that was absent from 73 control canine whole genome sequences. An additional 12 Black Russian Terriers with POANV were RAB3GAP1:c.743delC homozygotes. DNA samples from 249 Black Russian Terriers with no known signs of POANV were either heterozygotes or homozygous for the reference allele. Mutations in human RAB3GAP1 cause Warburg micro syndrome (WARBM), a severe developmental disorder characterized by abnormalities of the eye, genitals and nervous system including a predominantly axonal peripheral neuropathy. RAB3GAP1 encodes the catalytic subunit of a GTPase activator protein and guanine exchange factor for Rab3 and Rab18 respectively. Rab proteins are involved in membrane trafficking in the endoplasmic reticulum, axonal transport, autophagy and synaptic transmission. The neuronal vacuolation and membranous inclusions and vacuoles in axons seen in this canine disorder likely reflect alterations of these processes. Thus, this canine disease could serve as a model for WARBM and provide insight into its pathogenesis and treatment